Adjunct Material to Provide Heterogeneous Drug Elution

ABSTRACT

Adjunct material to provide drug elution is a variety of different temporal and/or spatial patterns is provided. In general, a biocompatible adjunct having a plurality of distinct regions having a plurality of distinct regions is configured to be delivered to tissue by deployment of staples in a cartridge body of a surgical stapler. Each of the distinct regions can be disposed at a different location on the adjunct material and can have a different adjunct construction. At least two of the regions releasably retain at least one medicant and each of the at least one medicants is releasable from one of the regions in a non-homogeneous manner with respect to at least one of time of release and location of release.

FIELD

The present disclosure relates generally to adjunct materials forheterogeneous medicant eluting.

BACKGROUND

Surgical staplers are used in surgical procedures to close openings intissue, blood vessels, ducts, shunts, or other objects or body partsinvolved in the particular procedure. The openings can be naturallyoccurring, such as passageways in blood vessels or an internal organlike the stomach, or they can be formed by the surgeon during a surgicalprocedure, such as by puncturing tissue or blood vessels to form abypass or an anastomosis, or by cutting tissue during a staplingprocedure.

Most staplers have a handle with an elongate shaft having a pair ofmovable opposed jaws formed on an end thereof for holding and formingstaples therebetween. The staples are typically contained in a staplecartridge, which can house multiple rows of staples and is oftendisposed in one of the two jaws for ejection of the staples to thesurgical site. In use, the jaws are positioned so that the object to bestapled is disposed between the jaws, and staples are ejected and formedwhen the jaws are closed and the device is actuated. Some staplersinclude a knife configured to travel between rows of staples in thestaple cartridge to longitudinally cut and/or open the stapled tissuebetween the stapled rows.

While surgical staplers have improved over the years, a number ofproblems still present themselves. One common problem is that leaks canoccur due to the staple forming holes when penetrating the tissue orother object in which it is disposed. Blood, air, gastrointestinalfluids, and other fluids can seep through the openings formed by thestaples, even after the staple is fully formed. The tissue being treatedcan also become inflamed due to the trauma that results from stapling.Still further, staples, as well as other objects and materials that canbe implanted in conjunction with procedures like stapling, generallylack some characteristics of the tissue in which they are implanted. Forexample, staples and other objects and materials can lack the naturalflexibility of the tissue in which they are implanted. A person skilledin the art will recognize that it is often desirable for tissue tomaintain as much of its natural characteristics as possible afterstaples are disposed therein.

In some instances, biologic materials have been used in conjunction withtissue stapling. However, the use of biologic materials presents anumber of additional problems. For example, it can be difficult tomaintain a location of the biologic material with respect to jaws of thestapler prior to and during staple ejection. It can also be difficult tokeep the biologic material at a desired location at the surgical siteafter stapling is completed. Further, it can be difficult to manufacturethe biologic material to a desired shape and thickness. Common plasticand molding manufacturing techniques are not generally conducive to themanufacture of thin biologic layers for use in conjunction with surgicalstaplers. The fragile nature of many biologic materials also makes themdifficult to use with surgical staplers because they lack structuralsupport.

Accordingly, there remains a need for improved devices and methods forstapling tissue, blood vessels, ducts, shunts, or other objects or bodyparts such that leaking and inflammation is minimized whilesubstantially maintaining the natural characteristics of the treatmentregion. There further remains a need for improved implantable materialsthat include biologics.

SUMMARY

The present disclosure relates generally to adjunct materials to providemedicants therefrom in heterogeneous temporal and spatial patterns.

In one aspect, a staple cartridge assembly for use with a surgicalstapler is provided that includes a cartridge body having a plurality ofstaple cavities, each staple cavity having a surgical staple disposedtherein, a biocompatible adjunct material releasably retained on thecartridge body, configured to be delivered to tissue by deployment ofthe staples in the cartridge body, and having a plurality of distinctregions, and an effective amount of at least one medicant disposedwithin and releasable from at least two of the regions. Each region fromthe plurality of distinct regions is at a different location on theadjunct material and each region has a different adjunct construction.Each of the at least one medicants is effective to provide a desiredeffect, and each of the at least one medicants is releasable from one ofthe regions in a non-homogeneous manner with respect to at least one oftime of release and location of release.

The staple cartridge assembly can vary in a number of ways. For example,a first one of the regions can contain a first medicant, a second one ofthe regions can contain a second medicant, and a third one of theregions can contain a third medicant, each region being at a differentlocation within the adjunct material. The first region can be configuredto commence release of the first medicant substantially immediately upondelivery of the adjunct material to tissue, the second region can beconfigured to commence release of the second medicant after release ofthe first medicant, and the third region can be configured to commencerelease of the third medicant after release of the second medicant. Insome aspects, the first region can be configured to complete delivery ofthe first medicant within about one day after delivery of the adjunctmaterial to tissue, the second region can be configured to deliver ofthe second medicant within a period of about one day after delivery ofthe adjunct material to tissue to about three days after delivery of theadjunct material to tissue, and the third region can be configured toinitiate delivery of the third medicant within about three days afterdelivery of the adjunct material to tissue. The first medicant can be ahemostatic agent. The second medicant can be an anti-inflammatory agent.

In some aspects, the cartridge body can have a slot formed along alongitudinal axis thereof that is configured to allow passage of atissue cutting element therethrough. The first region is positionedwithin a central portion of the adjunct material on either side of theslot and is configured to be separated by passage of the cutting elementthrough the slot such that release of the first medicant commencessubstantially simultaneously upon passage of the cutting element throughthe first region. The second region is in contact with a surface of thecartridge body, and the second medicant is effective to inhibit tissuegrowth adjacent the second region; and the third region is opposite thesecond region, and the third medicant is effective to promote tissuegrowth. The third medicant can be released after the first medicant.

In some aspects, the adjunct material can be formed of a fiber lattice,and each of the plurality of regions is formed of a different fiberlattice. The at least one medicant can be associated with the fiberlattice in a number of ways. For example, the at least one medicant canbe adhered to fibers in the fiber lattices, and each of the plurality ofregions can contain a different medicant. The medicant can be coated onthe fibers. In some implementations, the at least one fiber lattice canhave multiple drugs present in multiple degradable layers fibers withinthe at least one fiber lattice.

In other aspects, an end effector for a surgical instrument is providedthat in some implementations includes a first jaw having a cartridgebody removably attached thereto that has on a tissue-facing surfacethereof a plurality of staple cavities configured to seat staplestherein, a second jaw having an anvil with a plurality of staple formingcavities formed on a tissue-facing surface thereof, a biocompatibleadjunct material releasably retained on at least one of thetissue-facing surfaces of the cartridge body and the anvil and having aplurality of distinct regions, and an effective amount of at least onemedicant disposed within and releasable from at least two of theregions. At least one of the first and second jaws is movable relativeto the other. The biocompatible adjunct material is configured to bedelivered to tissue by deployment of the staples in the cartridge body.Each of the at least one medicants is effective to provide a desiredeffect, and each of the at least one medicants is releasable from one ofthe regions in a non-homogeneous manner with respect to at least one oftime of release and location of release.

The biocompatible adjunct material of the effector can vary in a numberof different ways. For example, a first one of the regions can contain afirst medicant, a second one of the regions can contain a secondmedicant, and a third one of the regions can contain a third medicant,each region being at a different location within the adjunct material.The first region can be configured to commence release of the firstmedicant substantially immediately upon delivery of the adjunct materialto tissue, the second region can be configured to commence release ofthe second medicant after release of the first medicant, and the thirdregion can be configured to commence release of the third medicant afterrelease of the second medicant. In some aspects, the first region can beconfigured to complete delivery of the first medicant within about oneday after delivery of the adjunct material to tissue, the second regioncan be configured to deliver of the second medicant within a period ofabout one day after delivery of the adjunct material to tissue to aboutthree days after delivery of the adjunct material to tissue, and thethird region can be configured to initiate delivery of the thirdmedicant within about three days after delivery of the adjunct materialto tissue. The first medicant can be a hemostatic agent. The secondmedicant can be an anti-inflammatory agent.

BRIEF DESCRIPTION OF DRAWINGS

The present disclosure will be more fully understood from the followingdetailed description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 is a perspective view of one embodiment of a surgical stapler;

FIG. 2 is an exploded view of a distal portion of the surgical staplerof FIG. 1;

FIG. 3 is a perspective view of a firing bar of the surgical stapler ofFIG. 1, the firing bar having an E-beam at a distal end thereof;

FIG. 4 is a perspective view of another embodiment of a surgicalstapler;

FIG. 5 is a perspective view of yet another embodiment of a surgicalstapler;

FIG. 6 is a graphical representation of an embodiment of an adjunctmaterial with different types of medicants encapsulated using differentrelease mechanisms before medicant release;

FIG. 7 is a graphical representation of the adjunct material of FIG. 6,showing release of a first medicant;

FIG. 8 is a graphical representation of the adjunct material of FIG. 6,showing release of a second medicant;

FIG. 9 is another graphical representation of an embodiment of anadjunct material with different types of medicants encapsulated usingdifferent release mechanisms before medicant release;

FIG. 10 is a graphical representation of the adjunct material of FIG. 9,showing release of the medicants as a result of absorption of a firstcoating;

FIG. 11 is a graphical representation of the adjunct material of FIG. 9,showing release of the medicants as a result of absorption of a secondcoating;

FIG. 12 is a graphical representation of an adjunct material includingtop and bottom layers of an absorbable polymer having differentdegradation rates;

FIG. 13 is a graphical representation of the adjunct material of FIG.12, showing a top layer partially degraded;

FIG. 14 is a graphical representation of the adjunct material of FIG.12, showing a bottom layer partially degraded after the top layer hasbeen degraded;

FIG. 15 is a graphical representation of an adjunct material configuredto release at least one medicant in response to at least oneenvironmental condition;

FIG. 16 is a graphical representation of the adjunct material of FIG.15, showing the at least one medicant partially released from theadjunct material in response to at least one environmental condition;

FIG. 17 is another graphical representation of the adjunct material ofFIG. 15, showing the at least one medicant substantially entirelyreleased from the adjunct material in response to at least oneenvironmental condition;

FIG. 18 is a graphical representation of an adjunct material configuredto release at least one medicant by changing its conformation;

FIG. 19 is a graphical representation of the adjunct material of FIG.18, showing the adjunct material with its conformation changes and theat least one medicant partially released;

FIG. 20 is a graphical representation of an adjunct material includingmultiple fibers associated with vessels having at least one medicantdisposed therein;

FIG. 21 is a graphical representation of the adjunct material of FIG.20, showing the at least one medicant released from the adjunct materialunder the effect of strain;

FIG. 22 is a graphical representation of an adjunct material configuredto release at least one medicant in response to strain applied to theadjunct material;

FIG. 23 is a graphical representation of the adjunct material of FIG.22, showing the at least one medicant being released in response tostrain applied to the adjunct material;

FIG. 24 is a graphical representation of a vessel having at least onemedicant encapsulated therein;

FIG. 25 is a graphical representation of the vessel of FIG. 24, showingthe at least one medicant being released in response to strain appliedto the vessel;

FIG. 26 is a graphical representation of an adjunct material configuredto release at least one medicant when the adjunct material changes itsconformation;

FIG. 27 is a graphical representation of the adjunct material of FIG.26, showing the at least one medicant being released in response achange in the conformation of the adjunct material;

FIG. 28 is another graphical representation of an adjunct materialconfigured to release at least one medicant when the adjunct materialchanges its conformation;

FIG. 29 is a graphical representation of the adjunct material of FIG.28, showing the at least one medicant being released in response achange in the conformation of the adjunct material;

FIG. 30 is a graphical representation of an adjunct material havingvessels configured to release at least one medicant encapsulated thereinin a non-homogeneous manner;

FIG. 31 is a graphical representation of a vessel configured to releasemultiple medicants encapsulated at different layers thereof in anon-homogeneous manner;

FIG. 32 is a graphical representation of an adjunct material havingdifferent portions configured to release at least one medicant in anon-homogeneous manner;

FIG. 33 is another graphical representation of an adjunct materialhaving different portions configured to release at least one medicant ina non-homogeneous manner;

FIG. 34 is a graphical representation of a side view of the adjunctmaterial of FIG. 33;

FIG. 35 is a graphical representation of a side view of an adjunctmaterial having different portions configured to release at least onemedicant in a non-homogeneous manner;

FIG. 36 is another graphical representation of a side view of an adjunctmaterial having different portions configured to release at least onemedicant in a non-homogeneous manner;

FIG. 37 is a graphical representation of an adjunct material havingdifferent concentric regions configured to release at least one medicantat different rates;

FIG. 38 is a graphical representation of an adjunct material havingdifferent radial regions configured to release at least one medicant atdifferent rates;

FIG. 39 is another graphical representation of an adjunct materialhaving different concentric regions configured to release at least onemedicant at different rates;

FIG. 40 is a graphical representation of an embodiment of wound healingover time with doses of medicants;

FIG. 41 is a graphical representation of a hemostatic stage in the woundhealing of FIG. 40;

FIG. 42 is a graphical representation of a portion of an inflammationstage in the wound healing of FIG. 40;

FIG. 43 is a graphical representation of another portion of theinflammation stage in the wound healing of FIG. 40;

FIG. 44 is a graphical representation of a proliferation stage in thewound healing of FIG. 40;

FIG. 45 is a perspective, partial cutaway view of an implementation ofan implantable adjunct that includes a plurality of heterogeneous layersor portions;

FIG. 46 is a graph showing an implementation of an elution profile ofthe adjunct of FIG. 45;

FIG. 47 is a graph showing another implementation of an elution profileof the adjunct of FIG. 45;

FIG. 48 is a graph showing yet another implementation of an elutionprofile of the adjunct of FIG. 45;

FIG. 49 is a perspective view of an implementation of an implantableadjunct including a plurality of heterogeneous regions;

FIG. 50 is a cross-sectional side view of the adjunct of FIG. 49 stapledto tissue;

FIG. 51 is a perspective view of the adjunct and tissue of FIG. 50;

FIG. 52 is a cross-sectional perspective view of an anvil of a surgicalinstrument releasably associated with an adjunct containing at least onemedicant; and

FIG. 53 is a cross-sectional view of a portion of the anvil of FIG. 52.

DETAILED DESCRIPTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Further, in the present disclosure, like-named components of theembodiments generally have similar features, and thus within aparticular embodiment each feature of each like-named component is notnecessarily fully elaborated upon. Additionally, to the extent thatlinear or circular dimensions are used in the description of thedisclosed systems, devices, and methods, such dimensions are notintended to limit the types of shapes that can be used in conjunctionwith such systems, devices, and methods. A person skilled in the artwill recognize that an equivalent to such linear and circular dimensionscan easily be determined for any geometric shape. Sizes and shapes ofthe systems and devices, and the components thereof, can depend at leaston the anatomy of the subject in which the systems and devices will beused, the size and shape of components with which the systems anddevices will be used, and the methods and procedures in which thesystems and devices will be used.

It will be appreciated that the terms “proximal” and “distal” are usedherein with reference to a user, such as a clinician, gripping a handleof an instrument. Other spatial terms such as “front” and “back”similarly correspond respectively to distal and proximal. It will befurther appreciated that for convenience and clarity, spatial terms suchas “vertical” and “horizontal” are used herein with respect to thedrawings. However, surgical instruments are used in many orientationsand positions, and these spatial terms are not intended to be limitingand absolute.

Various exemplary devices and methods are provided for performingsurgical procedures. In some embodiments, the devices and methods areprovided for open surgical procedures, and in other embodiments, thedevices and methods are provided for laparoscopic, endoscopic, and otherminimally invasive surgical procedures. The devices may be fireddirectly by a human user or remotely under the direct control of a robotor similar manipulation tool. However, a person skilled in the art willappreciate that the various methods and devices disclosed herein can beused in numerous surgical procedures and applications. Those skilled inthe art will further appreciate that the various instruments disclosedherein can be inserted into a body in any way, such as through a naturalorifice, through an incision or puncture hole formed in tissue, orthrough an access device, such as a trocar cannula. For example, theworking portions or end effector portions of the instruments can beinserted directly into a patient's body or can be inserted through anaccess device that has a working channel through which the end effectorand elongated shaft of a surgical instrument can be advanced.

It can be desirable to use one or more biologic materials and/orsynthetic materials, collectively referred to herein as “adjuncts,” inconjunction with surgical instruments to help improve surgicalprocedures. While a variety of different surgical end effectors canbenefit from the use of adjuncts, in some exemplary embodiments the endeffector can be a surgical stapler. When used in conjunction with asurgical stapler, the adjunct(s) can be disposed between and/or on jawsof the stapler, incorporated into a staple cartridge disposed in thejaws, or otherwise placed in proximity to the staples. When staples aredeployed, the adjunct(s) can remain at the treatment site with thestaples, in turn providing a number of benefits. For example, theadjunct(s) may reinforce tissue at the treatment site, preventingtearing or ripping by the staples at the treatment site. Tissuereinforcement may be needed to keep the staples from tearing through thetissue if the tissue is diseased, is healing from another treatment suchas irradiation, medications such as chemotherapy, or other tissueproperty altering situation. In some instances, the adjunct(s) mayminimize tissue movement in and around the staple puncture sites thatcan occur from tissue deformation that occurs after stapling (e.g., lunginflation, gastrointestinal tract distension, etc.). It will berecognized by one skilled in the art that a staple puncture site mayserve as a stress concentration and that the size of the hole created bythe staple will grow when the tissue around it is placed under tension.Restricting the tissues movement around these puncture sites canminimize the size the holes may grow to under tension. In someinstances, the adjunct(s) can be configured to wick or absorb beneficialfluids, e.g., sealants, blood, glues, that further promote healing, andin some instances, the adjunct(s) can be configured to degrade to form agel, e.g., a sealant, that further promotes healing. In some instances,the adjunct(s) can be used to help seal holes formed by staples as theyare implanted into tissue, blood vessels, and various other objects orbody parts. The adjunct(s) may also affect tissue growth through thespacing, positioning and/or orientation of any fibers or strandsassociated with the adjunct(s).

The adjunct(s) can also have medicant(s) thereon and/or therein. Themedicant(s) can vary depending on the desired effect of the medicant(s)on the surrounding tissue. As a non-limiting example, medicant(s) can beprovided to influence hemostasis, inflammation, macrophages, and/orfibroblasts. Medicant(s) can be mixed or combined in any combination ora medicant can be provided alone, again depending on the desired effecton the tissue. The medicant(s) can be eluted from the adjunct(s) in avariety of different ways. As non-limiting examples, coatings on theadjunct(s) can be varied to be absorbed at different times, therebyreleasing the medicant(s) at different times; the adjunct(s) can bevaried to allow diffusion of the medicant(s) across the adjunct(s) atvarying rates; the adjunct(s) can vary in molecular weight and/orphysical characteristics to cause release of the medicant(s) atdifferent times; etc.

Surgical Stapling Instruments

A variety of surgical instruments can be used in conjunction with theadjunct(s) and/or medicant(s) disclosed herein. “Adjuncts” are alsoreferred to herein as “adjunct materials.” The surgical instruments caninclude surgical staplers. A variety of surgical staplers can be used,for example linear surgical staplers and circular staplers. In general,a linear stapler can be configured to create longitudinal staple linesand can include elongate jaws with a cartridge coupled theretocontaining longitudinal staple rows. The elongate jaws can include aknife or other cutting element capable of creating a cut between thestaple rows along tissue held within the jaws. In general, a circularstapler can be configured to create annular staple lines and can includecircular jaws with a cartridge containing annular staple rows. Thecircular jaws can include a knife or other cutting element capable ofcreating a cut inside of the rows of staples to define an openingthrough tissue held within the jaws. The staplers can be used in avariety of different surgical procedures on a variety of tissues in avariety of different surgical procedures, for example in thoracicsurgery or in gastric surgery.

FIG. 1 illustrates one example of a linear surgical stapler 10 suitablefor use with one or more adjunct(s) and/or medicant(s). The stapler 10generally includes a handle assembly 12, a shaft 14 extending distallyfrom a distal end 12 d of the handle assembly 12, and an end effector 30at a distal end 14 d of the shaft 14. The end effector 30 has opposedlower and upper jaws 32, 34, although other types of end effectors canbe used with the shaft 14, handle assembly 12, and components associatedwith the same. The lower jaw 32 has a staple channel 56 configured tosupport a staple cartridge 40, and the upper jaw 34 has an anvil surface33 that faces the lower jaw 32 and that is configured to operate as ananvil to help deploy staples of the staple cartridge 40 (the staples areobscured in FIG. 1 and FIG. 2). At least one of the opposed lower andupper jaws 32, 34 is moveable relative to the other lower and upper jaws32, 34 to clamp tissue and/or other objects disposed therebetween. Insome implementations, one of the opposed lower and upper jaws 32, 34 maybe fixed or otherwise immovable. In some implementations, both of theopposed lower and upper jaws 32, 34 may be movable. Components of afiring system can be configured to pass through at least a portion ofthe end effector 30 to eject the staples into the clamped tissue. Invarious implementations a knife blade 36 or other cutting element can beassociated with the firing system to cut tissue during the staplingprocedure.

Operation of the end effector 30 can begin with input from a user, e.g.,a clinician, a surgeon, etc., at the handle assembly 12. The handleassembly 12 can have many different configurations designed tomanipulate and operate the end effector 30 associated therewith. In theillustrated example, the handle assembly 12 has a pistol-grip typehousing 18 with a variety of mechanical and/or electrical componentsdisposed therein to operate various features of the instrument 10. Forexample, the handle assembly 12 can include a rotation knob 26 mountedadjacent a distal end 12 d thereof which can facilitate rotation of theshaft 14 and/or the end effector 30 with respect to the handle assembly12 about a longitudinal axis L of the shaft 14. The handle assembly 12can further include clamping components as part of a clamping systemactuated by a clamping trigger 22 and firing components as part of thefiring system that are actuated by a firing trigger 24. The clamping andfiring triggers 22, 24 can be biased to an open position with respect toa stationary handle 20, for instance by a torsion spring. Movement ofthe clamping trigger 22 toward the stationary handle 20 can actuate theclamping system, described below, which can cause the jaws 32, 34 tocollapse towards each other and to thereby clamp tissue therebetween.Movement of the firing trigger 24 can actuate the firing system,described below, which can cause the ejection of staples from the staplecartridge 40 disposed therein and/or the advancement the knife blade 36to sever tissue captured between the jaws 32, 34. A person skilled inthe art will recognize that various configurations of components for afiring system, mechanical, hydraulic, pneumatic, electromechanical,robotic, or otherwise, can be used to eject staples and/or cut tissue.

As shown in FIG. 2, the end effector 30 of the illustratedimplementation has the lower jaw 32 that serves as a cartridge assemblyor carrier and the opposed upper jaw 34 that serves as an anvil. Thestaple cartridge 40, having a plurality of staples therein, is supportedin a staple tray 37, which in turn is supported within a cartridgechannel of the lower jaw 32. The upper jaw 34 has a plurality of stapleforming pockets (not shown), each of which is positioned above acorresponding staple from the plurality of staples contained within thestaple cartridge 40. The upper jaw 34 can be connected to the lower jaw32 in a variety of ways, although in the illustrated implementation theupper jaw 34 has a proximal pivoting end 34 p that is pivotally receivedwithin a proximal end 56 p of the staple channel 56, just distal to itsengagement to the shaft 14. When the upper jaw 34 is pivoted downwardly,the upper jaw 34 moves the anvil surface 33 and the staple formingpockets formed thereon move toward the opposing staple cartridge 40.

Various clamping components can be used to effect opening and closing ofthe jaws 32, 34 to selectively clamp tissue therebetween. Asillustrated, the pivoting end 34 p of the upper jaw 34 includes aclosure feature 34 c distal to its pivotal attachment with the staplechannel 56. Thus, a closure tube 46, whose distal end includes ahorseshoe aperture 46 a that engages the closure feature 34 c,selectively imparts an opening motion to the upper jaw 34 duringproximal longitudinal motion and a closing motion to the upper jaw 34during distal longitudinal motion of the closure tube 46 in response tothe clamping trigger 22. As mentioned above, in various implementations,the opening and closure of the end effector 30 may be effected byrelative motion of the lower jaw 32 with respect to the upper jaw 34,relative motion of the upper jaw 34 with respect to the lower jaw 32, orby motion of both jaws 32, 34 with respect to one another.

The firing components of the illustrated implementation includes afiring bar 35, as shown in FIG. 3, having an E-beam 38 on a distal endthereof. The firing bar 35 is encompassed within the shaft 14, forexample in a longitudinal firing bar slot 14 s of the shaft 14, andguided by a firing motion from the handle 12. Actuation of the firingtrigger 24 can affect distal motion of the E-beam 38 through at least aportion of the end effector 30 to thereby cause the firing of staplescontained within the staple cartridge 40. As illustrated, guides 39projecting from a distal end of the E-Beam 38 can engage a wedge sled 47shown in FIG. 2, which in turn can push staple drivers 48 upwardlythrough staple cavities 41 formed in the staple cartridge 40. Upwardmovement of the staple drivers 48 applies an upward force on each of theplurality of staples within the cartridge 40 to thereby push the staplesupwardly against the anvil surface 33 of the upper jaw 34 and createformed staples.

In addition to causing the firing of staples, the E-beam 38 can beconfigured to facilitate closure of the jaws 32, 34, spacing of theupper jaw 34 from the staple cartridge 40, and/or severing of tissuecaptured between the jaws 32, 34. In particular, a pair of top pins anda pair of bottom pins can engage one or both of the upper and lower jaws32, 34 to compress the jaws 32, 34 toward one another as the firing bar35 advances through the end effector 30. Simultaneously, the knife 36extending between the top and bottom pins can be configured to severtissue captured between the jaws 32, 34.

In use, the surgical stapler 10 can be disposed in a cannula or port anddisposed at a surgical site. A tissue to be cut and stapled can beplaced between the jaws 32, 34 of the surgical stapler 10. Features ofthe stapler 10 can be maneuvered as desired by the user to achieve adesired location of the jaws 32,34 at the surgical site and the tissuewith respect to the jaws 32, 34. After appropriate positioning has beenachieved, the clamping trigger 22 can be pulled toward the stationaryhandle 20 to actuate the clamping system. The trigger 22 can causecomponents of the clamping system to operate such that the closure tube46 advances distally through at least a portion of the shaft 14 to causeat least one of the jaws 32, 34 to collapse towards the other to clampthe tissue disposed therebetween. Thereafter, the trigger 24 can bepulled toward the stationary handle 20 to cause components of the firingsystem to operate such that the firing bar 35 and/or the E-beam 38 areadvanced distally through at least a portion of the end effector 30 toeffect the firing of staples and optionally to sever the tissue capturedbetween the jaws 32, 34.

Another example of a surgical instrument in the form of a linearsurgical stapler 50 is illustrated in FIG. 4. The stapler 50 cangenerally be configured and used similar to the stapler 10 of FIG. 1.Similar to the surgical instrument 10 of FIG. 1, the surgical instrument50 includes a handle assembly 52 with a shaft 54 extending distallytherefrom and having an end effector 60 on a distal end thereof fortreating tissue. Upper and lower jaws 64, 62 of the end effector 60 canbe configured to capture tissue therebetween, staple the tissue byfiring of staples from a cartridge 66 disposed in the lower jaw 62,and/or to create an incision in the tissue. In this implementation, anattachment portion 67 on a proximal end of the shaft 54 can beconfigured to allow for removable attachment of the shaft 54 and the endeffector 60 to the handle assembly 52. In particular, mating features 68of the attachment portion 67 can mate to complementary mating features71 of the handle assembly 52. The mating features 68, 71 can beconfigured to couple together via, e.g., a snap fit coupling, a bayonettype coupling, etc., although any number of complementary matingfeatures and any type of coupling can be used to removably couple theshaft 54 to the handle assembly 52. Although the entire shaft 54 of theillustrated implementation is configured to be detachable from thehandle assembly 52, in some implementations, the attachment portion 67can be configured to allow for detachment of only a distal portion ofthe shaft 54. Detachable coupling of the shaft 54 and/or the endeffector 60 can allow for selective attachment of a desired end effector60 for a particular procedure, and/or for reuse of the handle assembly52 for multiple different procedures.

The handle assembly 52 can have one or more features thereon tomanipulate and operate the end effector 60. By way of non-limitingexample, a rotation knob 72 mounted on a distal end of the handleassembly 52 can facilitate rotation of the shaft 54 and/or the endeffector 60 with respect to the handle assembly 52. The handle assembly52 can include clamping components as part of a clamping system actuatedby a movable trigger 74 and firing components as part of a firing systemthat can also be actuated by the trigger 74. Thus, in someimplementations, movement of the trigger 74 toward a stationary handle70 through a first range of motion can actuate clamping components tocause the opposed jaws 62, 64 to approximate toward one another to aclosed position. In some implementations, only one of the opposed jaws62, 24 can move to the jaws 62, 64 to the closed position. Furthermovement of the trigger 74 toward the stationary handle 70 through asecond range of motion can actuate firing components to cause theejection of the staples from the staple cartridge 66 and/or theadvancement of a knife or other cutting element (not shown) to severtissue captured between the jaws 62, 64.

One example of a surgical instrument in the form of a circular surgicalstapler 80 is illustrated in FIG. 5. The stapler 80 can generally beconfigured and used similar to the linear staplers 10, 50 of FIG. 1 andFIG. 4, but with some features accommodating its functionality as acircular stapler. Similar to the surgical instruments 10, 50, thesurgical instrument 80 includes a handle assembly 82 with a shaft 84extending distally therefrom and having an end effector 90 on a distalend thereof for treating tissue. The end effector 90 can include acartridge assembly 92 and an anvil 94, each having a tissue-contactingsurface that is substantially circular in shape. The cartridge assembly92 and the anvil 94 can be coupled together via a shaft 98 extendingfrom the anvil 94 to the handle assembly 82 of the stapler 80, andmanipulating an actuator 85 on the handle assembly 82 can retract andadvance the shaft 98 to move the anvil 94 relative to the cartridgeassembly 92. The anvil 94 and cartridge assembly 92 can perform variousfunctions and can be configured to capture tissue therebetween, staplethe tissue by firing of staples from a cartridge 96 of the cartridgeassembly 92 and/or can create an incision in the tissue. In general, thecartridge assembly 92 can house a cartridge containing the staples andcan deploy staples against the anvil 94 to form a circular pattern ofstaples, e.g., staple around a circumference of a tubular body organ.

In one implementation, the shaft 98 can be formed of first and secondportions (not shown) configured to releasably couple together to allowthe anvil 94 to be detached from the cartridge assembly 92, which mayallow greater flexibility in positioning the anvil 94 and the cartridgeassembly 92 in a body of a patient. For example, the first portion ofthe shaft can be disposed within the cartridge assembly 92 and extenddistally outside of the cartridge assembly 92, terminating in a distalmating feature. The second portion of the shaft 84 can be disposedwithin the anvil 94 and extend proximally outside of the cartridgeassembly 92, terminating in a proximal mating feature. In use, theproximal and distal mating features can be coupled together to allow theanvil 94 and cartridge assembly 92 to move relative to one another.

The handle assembly 82 of the stapler 80 can have various actuatorsdisposed thereon that can control movement of the stapler. For example,the handle assembly 82 can have a rotation knob 86 disposed thereon tofacilitate positioning of the end effector 90 via rotation, and/or thetrigger 85 for actuation of the end effector 90. Movement of the trigger85 toward a stationary handle 87 through a first range of motion canactuate components of a clamping system to approximate the jaws, i.e.move the anvil 94 toward the cartridge assembly 92. Movement of thetrigger 85 toward the stationary handle 87 through a second range ofmotion can actuate components of a firing system to cause the staples todeploy from the staple cartridge assembly 92 and/or cause advancement ofa knife to sever tissue captured between the cartridge assembly 92 andthe anvil 94.

The illustrated examples of surgical stapling instruments 10, 50, and 80provide only a few examples of many different configurations, andassociated methods of use, that can be used in conjunction with thedisclosures provided herein. Although the illustrated examples are allconfigured for use in minimally invasive procedures, it will beappreciated that instruments configured for use in open surgicalprocedures, e.g., open linear staplers as described in U.S. Pat. No.8,317,070 entitled “Surgical Stapling Devices That Produce FormedStaples Having Different Lengths” and filed Feb. 28, 2007, can be usedin conjunction with the disclosures provided herein. Greater detail onthe illustrated examples, as well as additional examples of surgicalstaplers, components thereof, and their related methods of use, areprovided in U.S. Pat. Pub. No. 2013/0256377 entitled “Layer ComprisingDeployable Attachment Members” and filed Feb. 8, 2013, U.S. Pat. No.8,393,514 entitled “Selectively Orientable Implantable FastenerCartridge” and filed Sep. 30, 2010, U.S. Pat. No. 8,317,070 entitled“Surgical Stapling Devices That Produce Formed Staples Having DifferentLengths” and filed Feb. 28, 2007, U.S. Pat. No. 7,143,925 entitled“Surgical Instrument Incorporating EAP Blocking Lockout Mechanism” andfiled Jun. 21, 2005, U.S. Pat. Pub. No. 2015/0134077 entitled “SealingMaterials For Use In Surgical Stapling” and filed Nov. 8, 2013, entitled“Sealing Materials for Use in Surgical Procedures, and filed on Nov. 8,2013, U.S. Pat. Pub. No. 2015/0134076, entitled “Hybrid AdjunctMaterials for Use in Surgical Stapling,” and filed on Nov. 8, 2013, U.S.Pat. Pub. No. 2015/0133996, entitled “Positively Charged ImplantableMaterials and Method of Forming the Same,” and filed on Nov. 8, 2013,U.S. Pat. Pub. No. 2015/0129634, entitled “Tissue Ingrowth Materials andMethod of Using the Same,” and filed on Nov. 8, 2013, U.S. Pat. Pub. No.2015/0133995, entitled “Hybrid Adjunct Materials for Use in SurgicalStapling,” and filed on Nov. 8, 2013, U.S. patent application Ser. No.14/226,142, entitled “Surgical Instrument Comprising a Sensor System,”and filed on Mar. 26, 2014, and U.S. patent application Ser. No.14/300,954, entitled “Adjunct Materials and Methods of Using Same inSurgical Methods for Tissue Sealing,” and filed on Jun. 10, 2014, whichare hereby incorporated by reference herein in their entireties.

Implantable Adjuncts

As indicated above, various implantable adjuncts are provided for use inconjunction with surgical stapling instruments. The adjuncts can have avariety of configurations, and can be formed from various materials. Ingeneral, an adjunct can be formed from one or more of a film, a foam, aninjection molded thermoplastic, a vacuum thermoformed material, afibrous structure, and hybrids thereof. The adjunct can also include oneor more biologically-derived materials and one or more drugs. Each ofthese materials is discussed in more detail below.

An adjunct can be formed from a foam, such as a closed-cell foam, anopen-cell foam, or a sponge. An example of how such an adjunct can befabricated is from animal derived collagen, such as porcine tendon, thatcan then be processed and lyophilized into a foam structure. Examples ofvarious foam adjuncts are further described in previously mentioned U.S.Pat. No. 8,393,514 entitled “Selectively Orientable Implantable FastenerCartridge” and filed Sep. 30, 2010.

An adjunct can also be formed from a film formed from any suitablematerial or combination thereof discussed below. The film can includeone or more layers, each of which can have different degradation rates.Furthermore, the film can have various regions formed therein, forexample, reservoirs that can releasably retain therein one or moremedicants in a number of different forms. The reservoirs having at leastone medicant disposed therein can be sealed using one or more differentcoating layers which can include absorbable or non-absorbable polymers.The film can be formed in various ways, for example, it can be anextruded or a compression molded film.

An adjunct can also be formed from injection molded thermoplastic or avacuum thermoformed material. Examples of various molded adjuncts arefurther described in U.S. Pat. Pub. No. 2013/0221065 entitled “FastenerCartridge Comprising A Releasably Attached Tissue Thickness Compensator”and filed Feb. 8, 2013, which is hereby incorporated by reference in itsentirety. The adjunct can also be a fiber-based lattice which can be awoven fabric, knitted fabric or non-woven fabric such as a melt-blown,needle-punched or thermal-constructed loose woven fabric. An adjunct canhave multiple regions that can be formed from the same type of latticeor from different types of lattices that can together form the adjunctin a number of different ways. For example, the fibers can be woven,braided, knitted, or otherwise interconnected so as to form a regular orirregular structure. The fibers can be interconnected such that theresulting adjunct is relatively loose. Alternatively, the adjunct caninclude tightly interconnected fibers. The adjunct can be in a form of asheet, tube, spiral, or any other structure that can include compliantportions and/or more rigid, reinforcement portions. The adjunct can beconfigured such that certain regions thereof can have more dense fiberswhile others have less dense fibers. The fiber density can vary indifferent directions along one or more dimensions of the adjunct, basedon an intended application of the adjunct.

The adjunct can also be a hybrid construct, such as a laminate compositeor melt-locked interconnected fiber. Examples of various hybridconstruct adjuncts are further described in U.S. Pat. Pub. No.2013/0146643 entitled “Adhesive Film Laminate” and filed Feb. 8, 2013,and in U.S. Pat. No. 7,601,118 entitled “Minimally Invasive MedicalImplant And Insertion Device And Method For Using The Same” and filedSep. 12, 2007, which are hereby incorporated by reference in theirentireties.

Materials

The adjuncts in accordance with the described techniques can be formedfrom various materials. The materials can be used in various embodimentsfor different purposes. The materials can be selected in accordance witha desired therapy to be delivered to tissue so as to facilitate tissuein-growth. The materials described below can be used to form an adjunctin any desired combination.

The materials can include bioabsorbable and biocompatible polymers,including homopolymers and copolymers. Non-limiting examples ofhomopolymers and copolymers include p-dioxanone (PDO or PDS),polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA),polycaprolactone (PCL), trimethylene carbonate (TMC), and polylacticacid (PLA), poly(glycolic acid-co-lactic acid) (PLA/PGA) (e.g., PLA/PGAmaterials used in Vicryl, Vicryl Rapide, PolySorb, and Biofix),polyurethanes (such as Elastane, Biospan, Tecoflex, Bionate, andPellethane fibers), polyorthoesters, polyanhydrides (e.g., Gliadel andBiodel polymers), polyoxaesters, polyesteramides, and tyrosine-basedpolyesteramides. The copolymers can also include poly(lacticacid-co-polycaprolactone) (PLA/PCL), poly(L-lacticacid-co-polycaprolactone) (PLLA/PCL), poly(glycolic acid-co-trimethylenecarbonate) (PGA/TMC) (e.g., Maxon), Poly(glycolic acid-co-caprolactone)(PCL/PGA) (e.g., Monocryl and Capgly), PDS/PGA/TMC (e.g., Biosyn),PDS/PLA, PGA/PCL/TMC/PLA (e.g., Caprosyn), and LPLA/DLPLA (e.g.,Optima).

An adjunct can also include active agents, such as active cell culture(e.g., diced autologous tissue, agents used for stem cell therapy (e.g.,Biosutures and Cellerix S.L.), hemostatic agents, and tissue healingagents. Non-limiting examples of hemostatic agents can include cellulosesuch as oxidized Regenerated Cellulose (ORC) (e.g., Surgicel andInterceed), fibrin/thrombin (e.g., Thrombin-JMI, TachoSil, Tiseel,Floseal, Evicel, TachoComb, Vivostat, and Everest), autologous plateletplasma, gelatin (e.g., Gelfilm and Gelfoam), hyaluronic acid such asmicrofibers (e.g., yarns and textiles) or other structures based onhyaluronic acid, or hyaluronic acid-based hydrogels. The hemostaticagents can also include polymeric sealants such as, for example, bovineserum albumin and glutarldehyde, human serum albumin and polyethylenecross-linker, and ethylene glycol and trimethylene carbonate. Thepolymeric sealants can include FocalSeal surgical sealant developed byFocal Inc.

The adjuncts described herein can releasably retain therein at least onemedicant that can be selected from a large number of differentmedicants. Medicants include, but are not limited to, drugs or otheragents included within, or associated with, the adjunct that have adesired functionality. The medicants include, but are not limited to,for example, antimicrobial agents such as antibacterial and antibioticagents, antifungal agents, antiviral agents, anti-inflammatory agents,growth factors, analgesics, anesthetics, tissue matrix degenerationinhibitors, anti-cancer agents, hemostatic agents, and other agents thatelicit a biological response.

Non-limiting examples of antimicrobial agents include Ionic Silver,Aminoglycosides, Streptomycin, Polypeptides, Bacitracin, Triclosan,Tetracyclines, Doxycycline, Minocycline, Demeclocycline, Tetracycline,Oxytetracycline, Chloramphenicol, Nitrofurans, Furazolidone,Nitrofurantoin, Beta-lactams, Penicillins, Amoxicillin, Amoxicillin+,Clavulanic Acid, Azlocillin, Flucloxacillin, Ticarcillin,Piperacillin+tazobactam, Tazocin, Biopiper TZ, Zosyn, Carbapenems,Imipenem, Meropenem, Ertapenem, Doripenem, Biapenem,Panipenem/betamipron, Quinolones, Ciprofloxacin, Enoxacin, Gatifloxacin,Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic Acid,Norfloxacin, Sulfonamides, Mafenide, Sulfacetamide, Sulfadiazine, SilverSulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole,Sulfasalazine, Sulfisoxazole, Bactrim, Prontosil, Ansamycins,Geldanamycin, Herbimycin, Fidaxomicin, Glycopeptides, Teicoplanin,Vancomycin, Telavancin, Dalbavancin, Oritavancin, Lincosamides,Clindamycin, Lincomycin, Lipopeptide, Daptomycin, Macrolides,Azithromycin, Clarithromycin, Erythromycin, Roxithromycin,Telithromycin, Spiramycin, Oxazolidinones, Linezolid, Aminoglycosides,Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin,Paromycin, Paromomycin, Cephalosporins, Ceftobiprole, Ceftolozane,Cefclidine, Flomoxef, Monobactams, Aztreonam, Colistin, and Polymyxin B.

Non-limiting examples of antifungal agents include Triclosan, Polyenes,Amphotericin B, Candicidin, Filipin, Hamycin, Natamycin, Nystatin,Rimocidin, Azoles, Imidazole, Triazole, Thiazole, Allylamines,Amorolfin, Butenafine, Naftifine, Terbinafine, Echinocandins,Anidulafungin, Caspofungin, Micafungin, Ciclopirox, and Benzoic Acid.

Non-limiting examples of antiviral agents include uncoating inhibitorssuch as, for example, Amantadine, Rimantadine, Pleconaril; reversetranscriptase inhibitors such as, for example, Acyclovir, Lamivudine,Antisenses, Fomivirsen, Morpholinos, Ribozymes, Rifampicin; andvirucidals such as, for example, Cyanovirin-N, Griffithsin, Scytovirin,a-Lauroyl-L-arginine ethyl ester (LAE), and Ionic Silver.

Non-limiting examples of anti-inflammatory agents include non-steroidalanti-inflammatory agents (e.g., Salicylates, Aspirin, Diflunisal,Propionic Acid Derivatives, Ibuprofen, Naproxen, Fenoprofen, andLoxoprofen), acetic acid derivatives (e.g., Tolmetin, Sulindac, andDiclofenac), enolic acid derivatives (e.g., Piroxicam, Meloxicam,Droxicam, and Lomoxicam), anthranilic acid derivatives (e.g., MefenamicAcid, Meclofenamic Acid, and Flufenamic Acid), selective COX-2inhibitors (e.g., Celecoxib (Celebrex), Parecoxib, Rofecoxib (Vioxx),Sulfonanilides, Nimesulide, and Clonixin), immune selectiveanti-inflammatory derivatives, corticosteroids (e.g., Dexamethasone),and iNOS inhibitors.

Non-limiting examples of growth factors include those that are cellsignaling molecules that stimulate cell growth, healing, remodeling,proliferation, and differentiation. Exemplary growth factors can beshort-ranged (paracrine), long ranged (endocrine), or self-stimulating(autocrine). Further examples of the growth factors include growthhormones (e.g., a recombinant growth factor, Nutropin, Humatrope,Genotropin, Norditropin, Saizen, Omnitrope, and a biosynthetic growthfactor), Epidermal Growth Factor (EGF) (e.g., inhibitors, Gefitinib,Erlotinib, Afatinib, and Cetuximab), heparin-binding EGF like growthfactors (e.g., Epiregulin, Betacellulin, Amphiregulin, and Epigen),Transforming Growth Factor alpha (TGF-a), Neuroregulin 1-4, FibroblastGrowth Factors (FGFs) (e.g., FGF1-2, FGF2, FGF11-14, FGF18, FGF15/19,FGF21, FGF23, FGF7 or Keratinocyte Growth Factor (KGF), FGF10 or KGF2,and Phenytoin), Insuline-like Growth Factors (IGFs) (e.g., IGF-1, IGF-2,and Platelet Derived Growth Factor (PDGF)), Vascular Endothelial GrowthFactors (VEGFs) (e.g., inhibitors, Bevacizumab, Ranibizumab, VEGF-A,VEGF-B, VEGF-C, VEGF-D and Becaplermin).

Additional non-limiting examples of the growth factors includecytokines, such as Granulocyte Macrophage Colony Stimulating Factors(GM-CSFs) (e.g., inhibitors that inhibit inflammatory responses, andGM-CSF that has been manufactured using recombinant DNA technology andvia recombinant yeast-derived sources), Granulocyte Colony StimulatingFactors (G-CSFs) (e.g., Filgrastim, Lenograstim, and Neupogen), TissueGrowth Factor Beta (TGF-B), Leptin, and interleukins (ILs) (e.g., IL-1a,IL-1b, Canakinumab, IL-2, Aldesleukin, Interking, Denileukin Diftitox,IL-3, IL-6, IL-8, IL-10, IL-11, and Oprelvekin). The non-limitingexamples of the growth factors further include erythropoietin (e.g.,Darbepoetin, Epocept, Dynepo, Epomax, NeoRecormon, Silapo, andRetacrit).

Non-limiting examples of analgesics include Narcotics, Opioids,Morphine, Codeine, Oxycodone, Hydrocodone, Buprenorphine, Tramadol,Non-Narcotics, Paracetamol, acetaminophen, NSAIDS, and Flupirtine.

Non-limiting examples of anesthetics include local anesthetics (e.g.,Lidocaine, Benzocaine, and Ropivacaine) and general anesthetic.

Non-limiting examples of tissue matrix degradation inhibitors thatinhibit the action of metalloproteinases (MMPs) and other proteasesinclude MMP inhibitors (e.g., exogenous MMP inhibitors,hydroxamate-based MMP inhibitors, Batimastat (BB-94), Ilomastat(GM6001), Marimastat (BB2516), Thiols, Periostat (Doxycycline), SquaricAcid, BB-1101, Hydroxyureas, Hydrazines, Endogenous,Carbamoylphosphates, Beta Lactams, and tissue Inhibitors of MMPs(TIMPs)).

Non-limiting examples of anti-cancer agents include monoclonialantibodies, bevacizumab (Avastin), cellular/chemoattractants, alkylatingagents (e.g., Bifunctional, Cyclophosphamide, Mechlorethamine,Chlorambucil, Melphalan, Monofunctional, Nitrosoureas and Temozolomide),anthracyclines (e.g., Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mitoxantrone, and Valrubicin), cytoskeletal disrupters (e.g., Paclitaxeland Docetaxel), epothilone agents that limit cell division by inhibitingmicrotubule function, inhibitor agents that block various enzymes neededfor cell division or certain cell functions, histone deacetylaseinhibitors (e.g., Vorinostat and Romidepsin), topoisomerase I inhibitors(e.g., Irinotecan and Topotecan), topoisomerase II inhibitors (e.g.,Etoposide, Teniposide, and Tafluposide), kinase inhibitors (e.g.,Bortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib, andVismodegib), nucleotide analogs (e.g., Azacitidine, Azathioprine,Capecitabine, Cytarabine, Doxifluridine, Fluorouracil, 5-FU, Adrucil,Carac, Efudix, Efudex, Fluoroplex, Gemcitabine, Hydroxyurea,Mercaptopurine, and Tioguanine), peptide antibiotic agents that cleaveDNA and disrupt DNA unwinding/winding (e.g., Bleomycin and Actinomycin),platinum-based anti-neoplastic agents that cross link DNA which inhibitsDNA repair and/or synthesis (e.g., Carboplatin, Cisplatin, Oxaliplatin,and Eloxatin), retinoids (e.g., Tretinoin, Alitretinoin, andBexarotene), vinca alkaloids gents that inhibit mitosis and microtubuleformation (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine),anti-ileus agents, pro-motility agents, immunosuppresants (e.g.,Tacrolimus), blood aspect modifier agents (e.g., Vasodilator, Viagra,and Nifedipine), 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductaseinhibitors (e.g., Atorvastatin), and anti-angiogenesis agents.

Exemplary medicants also include agents that passively contribute towound healing such as, for example, nutrients, oxygen expelling agents,amino acids, collageno synthetic agents, Glutamine, Insulin, Butyrate,and Dextran. Exemplary medicants also include anti-adhesion agents,non-limiting examples of which include Hyaluronic acid/Carboxymethylcellulose (seprafilm), Oxidized Regenerated Cellulose (Interceed), andIcodextrin 4% (Extraneal, Adept).

Drug Release

An adjunct in accordance with the described techniques can be associatedwith at least one medicant in a number of different ways, so as toprovide a desired effect, such as on tissue in-growth, in a desiredmanner. The at least one medicant can be configured to be released fromthe adjunct in multiple spatial and temporal patterns to trigger adesired healing process at a treatment site. The medicant can bedisposed within, bonded to, incorporated within, dispersed within, orotherwise associated with the adjunct. For example, the adjunct can haveone or more regions releasably retaining therein one or more differentmedicants. The regions can be distinct reservoirs of various sizes andshapes and retaining medicants therein in various ways, or otherdistinct or continuous regions within the adjuncts. In some aspects, aspecific configuration of the adjunct allows it to releasably retaintherein a medicant or more than one different medicant.

Regardless of the way in which the medicant is disposed within theadjunct, an effective amount of the at least one medicant can beencapsulated within a vessel, such as a pellet which can be in the formof microcapsules, microbeads, or any other vessel. The vessels can beformed from a bioabsorbable polymer.

Targeted delivery and release of at least one medicant from an adjunctcan be accomplished in a number of ways which depend on various factors.In general, the at least one medicant can be released from the adjunctmaterial as a bolus dose such that the medicant is releasedsubstantially immediately upon delivery of the adjunct material totissue. Alternatively, the at least one medicant can be released fromthe adjunct over a certain duration of time, which can be minutes,hours, days, or more. A rate of the timed release and an amount of themedicant being released can depend on various factors, such as adegradation rate of a region from which the medicant is being released,a degradation rate of one or more coatings or other structures used toretains the medicant within the adjuncts, environmental conditions at atreatment site, and various other factors. In some aspects, when theadjunct has more than one medicant disposed therein, a bolus doserelease of a first medicant can regulate a release of a second medicantthat commences release after the first medicant is released. The adjunctcan include multiple medicants, each of which can affect the release ofone or more other medicants in any suitable way.

Release of at least one medicant as a bolus dose or as a timed releasecan occur or begin either substantially immediately upon delivery of theadjunct material to tissue, or it can be delayed until a predeterminedtime. The delay can depend on a structure and properties of the adjunctor one or more of its regions.

An adjunct material can be configured to have a structure thatfacilitates distribution of effective amounts of one or more medicantscarried within the adjunct to provide a desired effect. For example, thetargeted delivery of the medicants can be accomplished by incorporatingthe medicants into regions (e.g., reservoirs such as pores or otherstructures) within the adjunct formed in a pattern that allows a certainspatial distribution of the medicants upon their delivery. The medicantsdisposed within the reservoir can be incorporated into distinct vessels.A reservoir can include more than one type of different medicants. Theone or more medicants can be eluted from the adjunct in a homogeneousmanner or in heterogeneous spatial and/or temporal manner to deliver adesired therapy. The structure of the adjunct and the way in which themedicants are released therefrom can be used to influence or controltissue re-growth. Moreover, the tissue regrowth can be encouraged incertain locations at the treatment site and discouraged at otherlocations at the treatment site.

FIG. 6 through FIG. 8 illustrate a biocompatible adjunct 100 havingmultiple pores carrying different medicants that are encapsulated withinthe pores disposed at different locations and using different absorbablecoatings. The coatings can absorb, dissolve or otherwise disintegrate atdifferent times after delivery of the adjunct 100 to a treatment siteand staple deployment so as to allow the medicants to also release atdifferent times and in different directions. Thus, the medicants can bereleased from the adjunct 100 in a non-homogeneous manner. For example,one of the medicants can be released immediately after delivery and/orstaple deployment whereas one or more of other medicants can be releasedat a later time, such as over a predetermined release profile. Therelease of these subsequently released medicants can be controlled by ordepend upon the release of the first medicant. The opposite sides of theadjunct 100 can be covered by coatings (or be formed of materials)having different absorption rates such that certain medicant(s) arereleased on one side of the adjunct while other medicant(s) are releasedon another side of the adjunct. This provides a more controlled andtargeted way of delivering therapies to tissue.

In this example, the adjunct 100 is in the form of a layer havingmultiple porous regions, two of which are shown by way of example aspores 101, 103. As shown in FIG. 6, the porous regions 101, 103 carryrespective first and second medicants 102, 104 which can be differentmedicants. It should be appreciated that the adjunct 100 has multipleporous regions which can carry the medicants 102, 104 in an alternatingmanner or in any other patterns.

As shown in FIG. 6, a first side 100 a of the adjunct 100 has coatingsA, C such that the coating A seals the porous region 101 with the firstmedicant 102 and the coating C seals the porous region 103 with thesecond medicant 104. A second, opposite side 100 b of the adjunct 100 iscovered by a coating B. In the illustrated example, the coatings A, B, Cthat create a barrier that affects release of a medicant can be selectedsuch that the coating A absorbs first after the staple deployment, thecoating B absorbs after the coating A has been at least partiallyabsorbed, and the coating C is not absorbable.

As shown in FIG. 7, after the delivery and/or staple deployment, thecoating A is first absorbed so as to allow the first medicant 102 to bereleased from the porous region 101 at the first side 100 a of theadjunct 100. For example, if the first side 100 a is a tissue-contactingsurface, the first medicant 102 can be a medicant that promotes healingat the treatment site. Subsequently, after a certain time period, thecoating B can be absorbed so as to allow the second medicant 104 to bereleased from the porous region 103 at the second side 100 b of theadjunct 100, as shown in FIG. 8. For example, if the second side 100 bis a non-tissue-contacting surface, the second medicant 104 can be amedicant that prevents adhesion. As also shown in FIG. 8, the coating Cseals the porous region 103 at the first side 100 a and thus preventsthe second medicant 104 from being released at the first side 100 a ofthe adjunct 100. Although in this example the coating C is notabsorbable, it can alternatively be absorbable after the coating B hasbeen absorbed and the second medicant 104 can been released at thesecond side 100 b. It should be appreciated that, to allow a porousregion to be exposed and a medicant to release, a coating can beabsorbed in its entirety or at least partially. A rate of absorption ofa coating can control a rate of release of a medicant.

A person skilled in the art will appreciate that more than two differentmedicants can be releasably incorporated into different porous regionsor other structures within an adjunct. The medicants can be retainedwithin the adjunct using various coatings that can be selected so as tocontrol rate and direction of release of the medicants.

An adjunct can include regions (e.g., pores or other reservoirs)releasably retaining a plurality of vessels, such as micro beads orother vessels, that have one or more medicants encapsulated therein.FIG. 9 through FIG. 11 illustrate an adjunct 108 including at least onemedicant encapsulated in a plurality of vessels that are releasablyretained by respective regions that regulate the dispersion of thevessels from the adjunct. The vessels can be micro capsules, microbeads, or any other types of vessels of a suitable size and shape. Eachvessel can have an absorbable outer layer that can degrade and thusrelease a medicant retained within that vessel once the vessels arereleased from an adjunct. The adjunct can be used to deliver medicantsin a non-homogeneous manner with respect to at least time of release andlocation of release.

As shown in FIG. 9, the adjunct 108 has multiple reservoirs or regions,five of which are shown as regions 109 a, 111 a, 113 a, 109 b, 111 bthat carry respective vessels 110, 112, 114, 110, 112. Thus, as shownschematically in FIG. 9, the regions 109 a, 109 b carry the same firsttype of vessels 110, the regions 111 a, 111 b carry the same second typeof vessels 112, and the region 113 a carries a third type of vessels114.

As shown in FIG. 9, on a first side 108 a of the adjunct 108, a layer ofcoating B1 seals the regions 111 a, 113 a and the region 111 b. A layerof a coating A1 is disposed over the entire first side 108 a and coversthe layers of the coating B1. On a second, opposite side 108 b of theadjunct 108, a layer of the coating B1 seals the region 109 a andanother layer of the coating B1 seals the region 109 b. A layer of acoating C1 seals the region 113 a on the second side 108 b. Similar tothe first side 108 a, the entire second side 108 b is covered by thecoating A1.

In this example, the coatings A1, B1, C1 have different degradation orabsorption rates such that the coating A1 begins to absorb first, upon adelivery of the adjunct to tissue, the coating B1 absorbs after thecoating A1 is at least partially absorbed, and the coating C1 is notabsorbable. The coating A1 can be selected such that it absorbssubstantially immediately after the delivery of the adjunct to tissue orat some later time. The coating A1 can be absorbed before the coating B1because the coating A1 is disposed on the surface of the adjunct and istherefore more accessible to water and/or other agents at a treatmentside. Other properties of the coating A1 can contribute to itsabsorption rate additionally or alternatively.

Because of the different absorption characteristics of the coating used,the coating A1 absorbs so as to release the first medicant 110 from theregions 109 a, 109 b at the first side 108 a and to release the secondmedicant 112 from the regions 111 a, 111 b at the second side 108 b, asshown in FIG. 10. As also shown in FIG. 10, the layers of the coating B1remain associated with the adjunct 108. As shown in FIG. 11, after thefirst medicant 110 is released at the first side 108 a and the secondmedicant 112 is released at the second side 108 b, the coating B1absorbs so as to release the third medicant 114 from the region 113 a atthe first side 108 a. In this way, different medicants can be deliveredat appropriate times to desired locations in tissue being treated. Itshould be appreciated that an adjunct can have any suitable pattern ofregions releasably retaining various medicants to create a desiredhealing process/profile.

In some aspects, alternatively or in addition to using various coatings,an adjunct can be in a form of a fiber lattice having regions withdifferent absorption characteristics. For example, each of the regionscan be in the form of fiber lattices having different absorption rates.A medicant associated with a fiber lattice can be released as the fiberlattice disintegrates. Because of the heterogeneous degradation ofabsorbable polymers forming the adjunct, the adjunct can be configuredsuch that one or more medicants associated therewith can release invarious spatial and temporal patterns. The medicant can be incorporatedinto pellets having a dissolvable coating (e.g., like a gobstopper) suchthat, as the coating is disintegrated, the medicant can be distributedas a bolus dose or as a time release dosage.

FIG. 12 through FIG. 14 illustrate an adjunct 116 having first (top) andsecond (bottom) layers 118, 120 formed from absorbable polymers havingdifferent degradation rates. For example, the first layer 118 can be alow molecular weight absorbable polymer that absorbs during a first timeperiod after the adjunct 116 is delivered to tissue and the second layer120 can be a high molecular weight absorbable polymer that absorbsduring a second time period after the first time period is completed.The first and second layers 118, 120 can be formed from differentpolymers or from the same type of polymer that is treated so as to formlayers or other structures having different degradation properties.

In the example of FIG. 12 through FIG. 14, the first layer 118 has afirst medicant 119 present therein, and the second layer 120 has secondmedicant 121 present therein. It should be appreciated, however, thateach of the first and second layers 118, 120 can include more than onetype of different medicant. The medicants can be retained in associationwith the first and second layers 118, 120 in a number of suitable ways.The first medicant 119 can be released first due to absorption of thefirst layer 118, as shown in FIG. 13 where the first layer 118 is shownpartially disintegrated such that the pellets containing the firstmedicant 119 are being released. As shown, the first layer 118 begins toabsorb from its surface that is more accessible to water and otheragents than portions of the first layer 118 removed farther from thesurface. After the first layer 118 has been entirely or partiallyabsorbed, the second layer 120 can commence to disintegrate from itssurface so as to release pellets harboring the second medicant 121, asshown in FIG. 14 where the second layer 120 is shown partiallydisintegrated and the pellets containing the second medicant 121 arebeing released from the adjunct 116.

In some aspects, an adjunct releasably retaining one or more medicantscan be configured such that one or more regions of the adjunctdisintegrate due to effects of temperature, pH, light, or otherenvironmental factors so as to release the medicant(s). Alternatively,the adjunct can break under the strain exerted upon one or more of itsportions. FIG. 15 through FIG. 17 illustrate an adjunct 122 having abody 123 retaining a medicant 124, a porous layer 125 disposed over thebody 123, and an absorbable outer film layer 126 disposed over theporous layer 125. The medicant 124 can be in the form of pellets (e.g.,solid micro-capsules or micro-beads or other vessels) releasablycarrying one or more medicants.

In the example illustrated, in its original configuration, the adjunct122 has a first width X1, as shown in FIG. 15. In such configuration,the outer film layer 126 restrains the porous layer 125 and pores in theporous layer 125 have a size that does not allow the medicant 124 toescape the adjunct 122. However, when the adjunct 122 is delivered totissue and the outer film layer 126 thus becomes exposed to pH,temperature, various agents, and/or other environmental conditions atthe treatment site, the absorbable outer film layer 126 can begin todisintegrate, as shown by a tear or opening 127 in the film layer 126 inFIG. 16. Additionally or alternatively, the outer film layer 126 canbreak upon strain due to deployment of staples or other mechanicalstrain on the adjunct 122.

Regardless of the specific factors that result in disintegration orbreaking of the outer film layer 126, the adjunct 122 can swell orotherwise alter its conformation such that its width increases from theoriginal width X1 to a larger width X2. As also shown in FIG. 15, thesize of the pores of porous layer 125 increases, allowing the pores'content, the pellets carrying the medicant 124, to pass through theenlarged pores and to be thus released from the adjunct 122.

A period of time during which the adjunct body 123 expands and thepellets with the medicant 124 are released can vary based on anabsorption rate of the outer film 126, properties of the adjunct body123, characteristics of the environment to which the adjunct 122 isdelivered, and other factors. After a certain time period, the outerfilm layer 126 can disintegrate and the adjunct 122 can expand furtherto have a width X3 such that the entirety or substantially the entiretyof the medicant 124 becomes released from the body 123 to deliverappropriate therapy or achieve the desired effect, as shown in FIG. 17.The adjunct 122 can be formed from at least one absorbable polymer(e.g., gelatin, cellulose, etc.) that regulates dispersion of thevessels. Thus, the adjunct 122 can act as a space filler that creates atemporary seal at a treatment site and is then dissolved to besubsequently replaced with tissue.

FIG. 18 and FIG. 19 illustrate another example of an adjunct 128releasably retaining different medicants and configured to release themedicants in a non-homogeneous manner. The adjunct 128 can be configuredto release the medicants due the effects of temperature, pH, variousagents, and/or other environmental factors upon the adjunct 128. Theadjunct 128 can change a conformation of one or more of its portions inresponse to the environmental factors. As shown in FIG. 18, the adjunct128 can have multiple regions or reservoirs two of which, first andsecond reservoirs 130, 132 carrying first and second medicants 131, 133,respectively, are shown. The reservoirs 130, 132 can be in the form oftubes, cavities, holes, or any other structures. The first reservoir 130is sealed by a first coating A2 at a first side 128 a of the adjunct 128and by a second coating B2 at a second side 128 b of the adjunct 128.The second reservoir 131 is sealed by the second coating B2 at the firstside 128 a and by the first coating A2 at the second side 128. In thisexample, the first and second coatings A2, B2 are selected such that thefirst coating A2 and its properties and/or configuration can be alteredby the effects of temperature, pH, active agents, and/or other factorsand thus open a reservoir that it seals. For example, the first coatingA2 can swell, soften, or otherwise become altered.

Accordingly, as shown in FIG. 19, upon the delivery of the adjunct 128to a treatment site, the first coating A2 can change its configurationsuch that it no longer seals the reservoir 130 at the first side 128 aof the adjunct 128 and it no longer seals the reservoir 132 at thesecond side 128 b of the adjunct 128. As a result, the first and secondmedicants 131, 133 are released at the first and second sides 128 a, 128b of the adjunct, respectively, as also shown in FIG. 19. The secondcoating B2 remains in place at least until the entirety of the medicantsare released into desired tissue locations, such preventing the releaseof the medicants.

In some aspects, the adjunct can be in the form of fibers or otherstructural components associated with one or more viscous fluidcomponents (e.g., vessels) retaining the medicant. The viscous componentcan be in a dry form (e.g., in a freeze-dried powder form) and it canre-hydrate upon deployment of the adjunct. As the viscous componentrehydrates, it can open and thus release a medicant. Additionally oralternatively, the vessel retaining the medicant can be disrupted bystrain such as, for example, mechanical breaking imposed thereon by thestaples or other means.

FIG. 20 and FIG. 21 illustrate an adjunct 140 in the form of multiplefibers, three of which are denoted by way of example as fibers 142, 144,146. As shown, each of the fibers 142, 144, 146 is associated with arespective one of vessels 143, 145, 147 retaining a medicant. Thevessels 143, 145, 147 can retain the same or different medicants. In theillustrated example, the vessels 143, 145, 147 are in the form ofirregularly shaped rounded beads having different sizes, however theycan be shaped in any other manner and can have various sizes. Thevessels can be applied to the fibers as a powder or they can be bonded,anchored to, or otherwise associated with the fiber strands. The vesselscan remain associated with the fibers or they can be released from thefibers to thus deliver a desired treatment using the adjunct.

As shown in FIG. 21, when strain is applied to the adjunct 140, which isschematically shown by arrows 141, the fibers can deform and vessels canbreak and release the medicant incorporated therein. The magnitude ofthe strain can control rates of release of the medicants. For example,as shown in FIG. 21, the vessel 143 is broken and a medicant 148 isbeing released. In some aspects, the vessels can be broken at differenttimes, depending on their size and/or other properties. In this example,the vessel 143 can be broken first to release the medicant 148 retainedtherein, as shown in FIG. 21, after which the smaller vessel 145 andthen even smaller vessel 147 can break thus releasing respectivemedicants at different times (not shown). However, depending on theapplied pressure and other factors, one or more vessels can breaksimultaneously. Furthermore, as mentioned above, the vessels 143, 145,147 can absorb at different times so as to release the respectivemedicants at different times.

In some aspects, an adjunct can have various surface textures of itsfibers and it can release one or more medicants in various ways toinfluence or control re-growth of tissue. The adjunct can be deliveredby staples carrying the adjunct thereon such that the medicants releasewhen the staple is deformed upon staple deployment. For example, FIG. 22illustrates an adjunct 150 having an outer layer or coating 152encapsulating an inner layer 154 disposed over a staple 151 of asurgical device used to deliver the adjunct 150. However, in someaspects, rather than being disposed over a staple, the adjunct 150 canbe disposed over a fiber lattice which can be folded into a tubular orother shape.

A first medicant can be retained between the outer coating 152 and theinner layer 154, and a second medicant can be incorporated into theinner layer 154. The inner layer 154 can be in the form of a flexiblemesh wound over the fiber 156. When strain is applied to the adjunct 150(e.g., when the staple 151 is deformed), as schematically shown by anarrow 153 in FIG. 23, the outer coating 152 can be caused to also deformand rupture. Upon the rupture of the outer coating 152, the firstmedicant retained between the outer coating 152 and the inner layer 154can release (155) the first medicant as a bolus dose. The secondmedicant incorporated into the inner layer 154 can commence its releaseas a timed release after the first medicant is released or during thetime when the first medicant is released. The release of the secondmedicant to tissue can be regulated by the release of the firstmedicant. The second medicant can alternatively be released at a bolusdose. It should be appreciated that the adjunct 150 can include onemedicant disposed within the inner layer 154 that can release as a bolusdose.

As mentioned above, an effective amount of at least one medicantdisposed within or associated with an adjunct can be retained withindistinct vessels carried by the adjunct. The vessels can be disposedwithin one or more regions of the adjunct or otherwise associatedtherewith. FIG. 24 and FIG. 25 illustrate an example of a vessel 158 inthe form of a pellet or capsule having an outer coating 159encapsulating therewithin at least one medicant 160. In this example,the vessel 158 has a spherical shape and resembles a gobstopper.However, it should be appreciated that the vessel can have any othershape. Furthermore, in some exemplary implementations, the outer coating159 can encapsulate an inner region including at least one bioabsorbablepolymer having at least one medicant incorporated therein. The vessels158 can include multiple layers having different degradation rates andreleasably retaining therein one or more medicants. Each of the layerscan retain a different medicant, or two or more of the layers can carrythe same medicant.

When a strain is applied to the vessel 158 as schematically shown by anarrow 161 in FIG. 25, the outer coating 159 can break or rupture suchthat its contents in the form of the at least one medicant 160 arereleased. Additionally or alternatively, the outer coating 159 canabsorb, dissolve or otherwise disintegrate upon exposure of the vessel158 to one or more environmental conditions such that the at least onemedicant 160 is released from the vessel 158.

FIG. 26 and FIG. 27 illustrate an example of an adjunct 162 in the formof a fiber lattice having a certain conformation that is changeable,such as by the action of water and/or other agents that the adjunct issubjected to at the treatment site. As shown in FIG. 26, the adjunct 162having a shape of a tightly wound spiral can retain therein one or morevessels carrying a medicant 164. The medicant 164 can be retained inassociation with the adjunct 162 by being held tightly by fibers of theadjunct. For example, the medicant can include a multilayeredmedicant/absorbable polymer structure where an outermost one of thelayers includes an absorbable polymer that can be bound to the fibers ofthe adjunct, e.g., bonding of one absorbable polymer to anotherabsorbable polymer, as will be appreciated by a person skilled in theart.

When the adjunct 162 is delivered at the treatment site, the woundfibers thereof can swell and increase in length, or elongate, such thatthe distances between the fibers increase and the adjunct 162 “unwinds”and releases the medicant 164 “trapped” within the adjunct 162, as shownin FIG. 27. The fibers of the adjunct 162 can unwind such that theentire adjunct 162 adopts a different conformation, like in the exampleof FIG. 26 and FIG. 27. However, in some aspects, the fibers of theadjunct can begin to unwind or fray from an end or other surface of theadjunct.

FIG. 28 and FIG. 29 illustrate another example of an adjunct 166 havinga medicant 168 releasably retained therein. In this example, the adjunct166 is in the form of a sheet-like fiber woven mesh. As shown in FIG.28, the tight fibers of the adjunct 166 in its original configurationallow the medicant 168 to be retained therein. When the adjunct 166 isdelivered at the treatment site, water and/or other agents, shownschematically as drops 167 a, 167 b in FIG. 28, can cause the fibers toswell and elongate such that the distances between the fibers increase,as shown in FIG. 29. In this way, the medicant 168 is released, as alsoshown in FIG. 29. A person skilled in the art will appreciate that theadjunct 166 can be formed from different types of fibers. The fibers canhave different absorption rates, density, direction, patterns, size, andother properties that are selected so as to provide desired tissuere-growth. While some regions of the adjunct can be configured torelease at least one medicant so as to encourage tissue re-growth, oneor more regions of the adjunct can be configured to release at least onemedicant so as to discourage tissue re-growth.

In aspects in which at least one medicant is disposed within a vesselformed from a bioabsorbable polymer coating encapsulating the medicant,the medicant can be configured to be released from the vessel at certaintime based on various factors. The factors can include, for example, adegradation rate of the bioabsorbable polymer, a volume of the vessel, asurface area of the vessel, environmental conditions in a physiologicalenvironment surrounding the vessel and responsiveness of thebioabsorbable polymer to such conditions, a number of layers of thebioabsorbable polymer, a concentration of the medicant, and a type ofassociation between the medicant and the bioabsorbable polymer.

FIG. 30 illustrates an example of first and second vessels 170, 172 thatcan be associated with a schematically shown adjunct 171. In thisexample, the first and second vessels 170, 172 are in the form ofspherical beads. However, other types of vessels can be usedadditionally or alternatively such that the adjunct 171 can include oneor more different types of vessels carrying different types ofmedicants. The first and second vessels 170, 172 have absorbable polymerouter coatings A3, B3 that have different degradation rates whichtherefore control release of first and second medicants D1, D2encapsulated within the coatings A3, B3 in different manners. Adegradation rate of the outer coating A3 can be higher than adegradation rate of the outer coating B3. Thus, the first medicant D1 isreleased from the first vessel 170 before the second medicant D2 isreleased from the second vessel 172. For example, the first medicant D1can be an inflammatory agent that is released within 1-2 days after theadjunct 171 is delivered to a treatment site. The second medicant D2 canbe an anti-inflammatory agent that is released within 3-5 days after thedelivery of the adjunct 171. In this way, the release of the medicantsD1, D2 from the first and second vessels 170, 172 can provide a desiredeffect on tissue in-growth.

A vessel having at least one medicant encapsulated therein can havemultiple medicants associated therewith in a number of different ways.FIG. 31 illustrates an example of a vessel 174 in a form of a spherehaving multiple concentric layers each carrying a respective at leastone medicant. In this example, as shown in FIG. 31, the vessel 174 has,from the outside to the inside, four distinct layers E1, E2, E3, E4having first, second, third, and fourth medicants F1, F2, F3, F4,respectively. Each of the layers E1, E2, E3, E4 can have differentdegradation rate, thickness, density, responsiveness to environmentalconditions, and other properties that control release of the medicantsdisposed therein. For example, the outermost first layer E1 can beconfigured to degrade first such the medicant is released first, and theother layers E2, E3, E4 can be configured to degrade such that an outerlayer degrades before an inner layer does.

As each layer degrades, a respective medicant incorporated therein isreleased. It should be appreciated that the layers can be selected suchthat at least one inner layer can start to degrade after only a portionof at least one outer layer has been degraded. The medicants F1, F2, F3,F4 disposed within the multi-layer vessel 174 can be different or atleast some of the medicants can be the same. The medicants can bereleased as a bolus dose or in other manners. For example, the firstmedicant F1 disposed within the first layer E1 can be released as abolus dose substantially immediately upon delivery of an adjunctretaining the vessel 174 to tissue. Release of the second medicant F2disposed within the second layer E2 can be regulated by the release ofthe first medicant F1.

A spatial distribution of medicants in an adjunct can vary depending ona type of the medicants and a desired effect on tissue in-growth.Targeted delivery of the medicants can be accomplished in a number ofways. For example, an adjunct can be configured to release one or moremedicants in a heterogeneous manner such that various medicants can bedelivered to tissue at different times, to facilitate desired healing.Different portions of the adjunct can be formed from different materialsor form the same material treated so as to have different absorptionrates.

FIG. 32 illustrates an adjunct 176 in the form of a laminate includingheterogeneous portions or layers having different degradation rates andincorporating different medicants. As shown, the adjunct 176 has a toplayer or portion 178 and a bottom layer or portion 180 that havedifferent degradation rates. Furthermore, each of the top and bottomportions 178, 180 can have various portions having degradation ratesthat vary in a distinct or continuous manner. The degradation rates canvary across the adjunct in a number of suitable ways that depend on adesired treatment effect to be provided by the adjunct.

In the example of FIG. 32, the top portion 178 of the adjunct 176 hastwo portions 178 a, 178 b having different degradation rates. The bottomportion 180 has two portions 180 a, 180 b having different degradationrates. Each of the portions can include a different medicant such that,as a portion degrades, a respective medicant is eluted or released. Thedegradation rates and distribution of the medicants within one or moreof the portions 178 a, 178 b, 180 a, 180 b can further vary in adistinct or continuous manner such that the adjunct 176 can provide anelution profile shown in a graph 177 in FIG. 32. As shown, a centralarea 182 of the adjunct 176 centered around a mid-portion 179 thereofhas an increased elution rate of one or more medicants that peaks at themid-portion 179, whereas smaller amount of the medicant(s) is elutedfrom opposite sides of the adjunct 176 along its length L. The increasedelution rate can be due to properties of the adjunct 176 at the centralarea 182 and the concentration of the medicants.

As further shown in FIG. 32, the adjunct 176 is configured to releasemedicants in different elution profiles along the length L thereof andalong a width W thereof. For example, the medicants can be releasedalong the width W as a bolus dose and along the length as a time-releasedose. Release of one or more of the medicants can regulate release of atleast one other of the medicants. However, the medicants can be releasedin any other manner, depending on a desired treatment to be delivered.

FIG. 33 illustrates another example of an adjunct 184 having top andbottom layers or portions 186, 188. Similar to the adjunct 176 in FIG.32, each of the top and bottom portions 186, 188 of the adjunct 184 canhave different medicants disposed therein. Thus, as shown in FIG. 33,the top portion 186 can have first and second medicants G1 and G2, atrespective portions thereof. The bottom portion 188 can have third andfourth medicants G3 and G4 at respective portions thereof disposed suchthat the third medicant G3 is in a portion disposed over a portioncarrying the fourth medicant G4, as also shown in FIG. 34.

FIG. 35 illustrates an example of a portion of an adjunct 185 that canbe similar to adjunct 176 (FIG. 32) or adjunct 184 (FIG. 33). As shownin FIG. 35, the adjunct 185 can have side-to-side portions 185 a, 185 bhaving different medicants G5, G6 disposed therein. FIG. 36 illustratesanother example of a portion of an adjunct 187 having an inner portion187 a and an outer portion 187 b having different medicants G7, G8disposed therein.

In some aspects, elution rates of at least one medicant from an adjuncthaving one or more distinct portions formed from at least onebioabsorbable polymer can depend on a position of the portions withinthe adjunct, a degradation rate of the at least one bioabsorbablepolymer, responsiveness of the at least one bioabsorbable polymer toenvironmental conditions, and an overall configuration of the adjunct.

FIG. 37 illustrates an example of an adjunct 190 in a form of a cylinderthat has outer and inner concentric layers 191, 192 which can be formedfrom different types of absorbable polymer and can have differentthickness and other properties. The outer and inner layers 191, 192 canhave different medicants B4, A4 disposed therein and that can bereleased from the respective layers 191, 192 at different times and atdifferent rates. In this example, an innermost cavity 193 lined by theinner layer 192 can be empty. The medicant A4 can be configured tocommence to release before the medicant B4 is released. It should beappreciated that, in some aspects, the outer and inner layers 191, 192can be disposed over a fiber.

FIG. 38 illustrates an example of a tubular adjunct 194 that hasmultiple radial portions formed from different types of absorbablepolymer. As shown, the adjunct 194 has an inner cavity 194 a having theradial portions disposed concentrically therearound. In the exampleillustrated, the portions can be formed from first and second types ofpolymer in an alternating manner, as shown by portions 195, 196 in FIG.38 formed from the first and second polymers, respectively. The portion195 formed from the first polymer has a medicant A5 disposed therein,the portion 197 formed from the second polymer has a medicant B5disposed therein, and other portions formed from the first and secondpolymers have the medicants A5, B5 disposed therein in the samealternating manner, as shown in FIG. 38. Similar to the examples before,the medicants A5, B5 can be released from the respective layers atdifferent times and at different rates. For example, the medicant A5 canbe configured to commence to release before the medicant B5 is released.

FIG. 39 illustrates an example of a tubular adjunct 197 similar toadjunct 190 (FIG. 37). As shown in FIG. 39, the adjunct 197 has outerand inner concentric layers 198, 199 which can be formed from differenttypes of absorbable polymer and can have different thickness and otherproperties. The outer and inner layers 198, 199 can have differentmedicants B6, A6 disposed therein and that can be released from therespective layers 198, 199 at different times and at different rates.For example, as shown in a graph 197 a in FIG. 39, the medicant A6 canrelease before the medicant B6 is released. Furthermore, the medicant A6can release at a higher dosage than the medicant B6, as also shown inthe graph 197 a.

In at least some implementations, a staple cartridge can include alubricant (e.g., sodium stearate or other lubricant) applied theretothat includes at least one medicant (e.g., LAE, Doxycycline, and/orother antimicrobial agent) releasable therefrom. The lubricant can beapplied to the staple cartridge as a spray and can coat the cartridgeand the staples releasably disposed therein. The lubricant including oneor more medicants may allow the medicant(s) to be applied to thestaples. In this way, the medicant(s) may be delivered to a targetedarea (e.g., along a staple line defined by the staples) where themedicant(s) may be best able to facilitate wound healing, as discussedherein. The lubricant including one or more medicants can be used withan adjunct including one or more medicants, which may facilitatetargeted wound healing.

Wound Healing

During performance of a surgical procedure, tissue of a patient can bewounded (e.g., cut, torn, punctured, etc.) in any of a variety of ways.The wounding may be an intended aspect of the surgical procedure, suchas in an anastomosis procedure and/or when tissue is cut and fastenedusing a surgical device such as a surgical stapler. The wounded tissuetypically heals over time in generally the same way for all patients.

Wound healing is traditionally considered to include four stages:hemostasis, inflammation, proliferation, and remodeling. The hemostasisstage generally involves blood clotting, e.g., stopping bleeding. Ingeneral, damaged blood vessels constrict to slow blood flow, plateletsaggregate to help seal the wound site, the platelets activate fibrin tofurther facilitate wound sealing, and a blood clot forms at the woundsite. The inflammation stage generally involves cleaning of the woundsite. In general, the immune system provides a response to the threat ofpossible infection at the wound site via signaling to defensive immunecells such as neutrophils and macrophages. The proliferation stagegenerally involves rebuilding tissue with tissue growth and angiogenesis(blood vessel growth). In general, fibroblasts arrive at the wound site,the fibroblasts lay down collagen, the fibroblasts release growthfactors that attract epithelial cells, and the epithelial cells attractendothelial cells. The remodeling stage, also referred to as amaturation stage, generally involves strengthening scar tissue at thewound site. In general, collagen fibers align and crosslink, and thescar matures to eventually fade away. Each of these four stages isdiscussed further below.

While each of wound healing's four stages involves a different aspect ofthe healing process, stages typically overlap with one another. Namely,each of the last three stages typically overlaps with its precedingstage, e.g., inflammation overlaps with hemostasis, proliferationoverlaps with inflammation, and remodeling overlaps with proliferation.The speed at which the transition between stages occurs generallyaffects the speed of overall wound healing and thus generally affectspatient recovery time, chances of complications arising, and/or patientcomfort. Similarly, the length of each of the four individual stagesgenerally affects the speed of overall wound healing and the patient'sgeneral recovery. In general, the slower the wound healing process, andin particular the longer it takes to begin the remodeling stage, themore likely that the wound will become infected, cause the patientdiscomfort, become a chronic wound, cause an ulcer, and/or developpathological scarring.

The hemostasis stage generally begins within minutes of the initialinjury, unless there are underlying clotting disorders, in which casehemostasis may be delayed. The hemostasis stage typically lasts for 30to 60 minutes before the inflammation stage begins (e.g., beforeneutrophils arrive, as discussed below) and typically ends hours afterthe injury, e.g., 2 to 6 hours post-injury. Poor hemostatic control thatresults in a longer hemostasis stage can lead to increased bleeding andtissue damage. Additionally, a prolonged hemostasis stage can result inadditional scar formation that delays the proliferation and remodelingstages.

In the hemostasis stage, injured blood vessels at the wound site aresealed. The blood vessels constrict in response to injury, e.g., inresponse to being cut, but this spasm ultimately relaxes. Bloodplatelets secrete vasoconstrictive substances to aid in this process.The platelets also form a stable clot sealing the damaged vessels. Underthe influence of adenosine diphosphate (ADP) leaking from the damagedtissue at the wound site, the blood platelets aggregate and adhere toexposed collagen. The blood platelets secrete factors, which interactwith and stimulate an intrinsic clotting cascade through the productionof thrombin, which in turn initiates the formation of fibrin fromfibrinogen. The clotting cascade occurs to achieve hemostasis, or stopblood loss by way of a fibrin clot. More particularly, the fibrin formsa mesh that strengthens the platelet aggregate into a stable hemostaticplug or clot, thereby reducing and/or preventing bleeding. The meshserves as a scaffold for invading cells, such as neutrophils,macrophages, fibroblasts, and endothelial cells, during the inflammationand proliferation stages. Additionally, the platelets secrete varioussoluble factors, such as chemokines, cytokines, and platelet-derivedgrowth factor (PDGF). This secretion generally initiates theinflammation stage of wound healing, as the soluble factors attractcells that phagocytize material (e.g., debris, microorganisms such asbacteria, and damaged tissue).

The clotting cascade occurs in the hemostasis stage just before theinflammatory stage begins. The inflammation stage typically beginswithin an hour of the injury and typically lasts for 2 to 6 days but canlast even longer, e.g., up to 10 days. The longer the inflammationstage, the more likely that additional scarring will occur, therebydelaying the proliferation and remodeling stages. During theinflammation stage, the wounded tissue can show various signs ofinflammation, such as erythema, heat, edema, pain, and functionaldisturbance. These signs can last for most or all of the inflammationstage. Accordingly, the longer the inflammation stage, the longer thetissue experiences these adverse effects of inflammation, which in turncan prolong patient discomfort and/or prolong the period of time inwhich the patient is particularly susceptible to infection. The adverseeffects of inflammation can be severe enough in some patients to causedeath. Inflammation must occur during proper wound healing, however, andits adverse effects tolerated in order for the final stages of woundhealing to commence.

In the inflammation stage, the cells attracted by the soluble factorssecreted in the hemostasis stage phagocytize material. Namely, immunecells including phagocytic cells, neutrophils, and macrophages destroymaterial in an effort to help prevent infection. The arrival ofneutrophils generally signals the start of the inflammation stage.Neutrophils typically arrive at the wound site within an hour ofwounding. The neutrophils are able to phagocytize debris andmicroorganisms and provide a first line of defense against infection.They are aided by local mast cells. Fibrin is broken down, and thedegradation products attract macrophages. Macrophages typically appear 1to 2 days post-injury. The macrophages are able to phagocytize bacteriaand provide a second line of defense against infection. The macrophagessecrete a variety of chemotactic factors and growth factors such asfibroblast growth factor (FGF), epidermal growth factor (EGF),transforming growth factor beta (TGF-β), and interleukin-1 (IL-1), whichare traditionally recognized as directing the subsequent proliferationand remodeling stages. In other words, the macrophages releaseangiogenic substances to help begin the proliferation stage to stimulatecapillary growth and granulation, thereby setting the stage for theremodeling stage. Lymphocytes (e.g., T lymphocytes) attracted to thewound site typically appear at the wound site after the macrophagesappear.

The proliferation stage typically begins 2 to 5 days post-injury andtypically lasts for 2 to 21 days. In the proliferation stage, themacrophages' secretion induces the proliferation of fibroblasts. Thefibroblasts enter the wound site and form an extracellular matrix (ECM)by excreting collagen and fibronectin. The wound is thus “rebuilt” withnew granulation tissue that includes the collagen and the ECM into whicha new network of blood vessels develop, a process traditionally known asangiogenesis. The collagen increases the strength of the wound.Accordingly, the sooner collagen can be produced, e.g., the sooner thatfibroblasts enter the wound area, the sooner the wound can gain strengthand thereby be less likely to cause any number of problems such asinfection and patient discomfort.

Concurrent with the ECM formation, epithelial cells (e.g.,keratinocytes) migrate from the wound's edge to cover the wound and forma barrier between the wound and its environment. In other words, theepithelial cells resurface the wound, in a process traditionally knownas epithelialization. The epithelial cells migrate over the granulationtissue but underneath the scab on the wound (if a scar was earlierformed). The epithelial cells must dissolve the clot, debris, and partsof the ECM in order to properly migrate over the wound. To facilitatetheir migration, the epithelial cells secrete a plasminogen activator,which activates plasminogen, turning it into plasmin to dissolve theclot, debris, and parts of the ECM. Additionally, since cells can onlymigrate over living tissue, the epithelial cells excrete collagenasesand proteases such as matrix metalloproteinases (MMPs) to dissolvedamaged parts of the ECM in their migrational path. In the final phaseof epithelialization, contraction of the wound occurs as the fibroblastsdifferentiate into myofibroblasts to form the protective outer layer, orstratum corneum. Contraction can last for days or several weeks andcontinues even after the wound is completely reepithelialized.Contraction is the main cause of scarring associated with wound healing.

The remodeling stage generally begins when the levels of collagenproduction and degradation equalize. In other words, remodelinggenerally begins once a scar has formed and the tensile strength of thewound has begun to increase. The remodeling stage typically begins 7 to21 days post-injury and typically lasts for at least 3 weeks and canlast for months or years depending on factors such as wound size andre-injury.

In the remodeling stage, the wound matures to become stronger, e.g., tohave increased tensile strength. In general, weaker type III collagen,which is common at the wound site in the proliferation stage, isreplaced by stronger type I collagen. This replacement generallyinvolves reorganizing, crosslinking, and aligning the temporary collagenfibers. As remodeling progresses, the scar disappears.

FIG. 40 illustrates a depiction of wound healing over time. An upperportion of FIG. 40 shows a first wound healing graph 200 of tissuestrength (tensile force F) versus time (t). A lower portion of FIG. 40shows a second wound healing graph 202 of medicant dose amount versustime (t). The first and second graphs 200, 202 are plotted with a sharedhorizontal axis to facilitate comparison of data shown in the first andsecond graphs 200, 202. Time zero (t=0) in the first and second graphs200, 202 represents a time of injury, e.g., when a wound occurs. A firsttissue strength F1 in the first graph 200 thus represents the tissue'sstrength at the wound at the time of injury.

The first graph 200 includes a first curve 204 of tissue strength overtime during typical wound healing, and includes a second curve 206 oftissue strength over time during accelerated wound healing in accordancewith at least some methods, systems, and devices provided herein. Thesecond curve 206 of accelerated wound healing can be achieved using oneor more doses of medicants provided in the second graph 202, asdiscussed further below. Stages of wound healing (a hemostasis stage208, an inflammation stage 210, and a proliferation stage 212) are shownin FIG. 40 with reference to the second graph 202, and hence also to thesecond curve 206 of the first graph 200. The first curve 204 in thefirst graph 200 has a different timing of hemostasis, inflammation, andproliferation stages, as discussed below.

The time scale in FIG. 40 is an example only. As discussed above, thetiming of wound healing can vary, e.g., the stages of wound healing canbegin at different times for different wounds and/or for differentpatients. FIG. 40 demonstrates that for the same wound in the samepatient, the wound's typical healing, as illustrated by the first curve204, is improved when one or more medicants are dosed to the patient inaccordance with the second graph 202, as illustrated by the second curve206. In other words, regardless of the time scale of the horizontal axisof the first and second graphs 200, 202, the dosing of one or moremedicants may provide for faster wound healing than typical woundhealing and may provide a shorter period of minimum tissue tensilestrength than typical wound healing.

As demonstrated by the first curve 204, typical wound healing involvesthe tissue having the first tissue strength F1 at time zero anddecreasing in strength over time to a minimum tissue strength F4 thatbegins during day four (5>t>4) during an inflammation stage and persistsuntil sometime during day six (7>t>6) before tissue strength begins togradually improve back toward the first tissue strength F1. The firsttissue strength F1 can be re-achieved during typical wound healing, asshown by the first curve 204, at some point during or after aproliferation stage. The tissue's strength begins to decrease from thefirst tissue strength F1 in response to inflammation, e.g., in responseto entry into the inflammation stage, during day one (2>t>1) andcontinues decreasing toward and/or remains at its lowest level F4 untilinflammation of the tissue begins to subside, e.g., until theproliferation stage begins, during day six. The tissue is thusdecreasing in strength and is at its most vulnerable to succumb to anynumber of inflammation's adverse effects for a relatively long period oftime that starts during day one and lasts into day six.

As demonstrated by the second curve 206, accelerated wound healing inaccordance with at least some embodiments of the methods, systems, anddevices provided herein involves the tissue having the first tissuestrength F1 at time zero and decreasing in strength over time to aminimum tissue strength F3 that begins during day three (4>t>3) duringthe inflammation stage 210 and persists until sometime during day four(5>t>4) before tissue strength begins to gradually improve back towardthe first tissue strength F1. The minimum tissue strength F3 in theaccelerated wound healing is greater than the minimum tissue strength F4in the typical wound healing. The tissue experiencing the acceleratedwound healing thus never has strength as low as that during typicalwound healing. In other words, the accelerated wound healing allows forless tissue weakening than typical wound healing. The tissue's strengthbegins to decrease from the first tissue strength F1 in response toinflammation, e.g., in response to entry into the inflammation stage210, during day one (2>t>1) and continues decreasing toward and/orremains at its lowest level F3 until inflammation begins to improve,e.g., until the proliferation stage 212 begins, during day four. Thetissue is thus decreasing in strength and is at its most vulnerable tosuccumb to any number of inflammation's adverse effects sooner and for ashorter period of time than typical wound healing, i.e., starting duringday one and lasting into day four instead of starting during day one andlasting into day six. In other words, the accelerated wound healing canprovide for a shorter inflammation stage than typical wound healing. Thetissue's strength may not increase back to its pre-wound tissue strengthF1 after the inflammation stage 210 in the accelerated healing but canincrease to a level close thereto, as shown by the second curve 206reaching a new maximum tissue strength F2 during the proliferation stage212.

The second graph 202 illustrates an example of doses of medicants thatcan be administered to the patient to achieve the accelerated woundhealing indicated by the second curve 206. The doses of medicants caninclude a dose of medicant A configured to facilitate hemostasis in thehemostasis stage 208 as also shown in FIG. 41; doses of medicant B,medicant B₁, medicant C, and medicant C₁ configured to facilitateinflammation in the inflammation stage 210 as also shown in FIG. 42;doses of medicant D and medicant D₁ configured to inhibit MMPs during amacrophages phase 214 of the inflammation stage 210 (e.g., during a timewhen macrophages are present and active at the wound site in theinflammation stage 210) as also shown in FIG. 43; a dose of medicant Econfigured to prevent inflammation in the proliferation stage 212 duringa fibroblasts phase 216 of the proliferation stage 212 (e.g., during atime when fibroblasts are present and active at the wound site in theproliferation stage 212) as also shown in FIG. 44; and a dose ofmedicant F configured to facilitate tissue growth in the proliferationstage 212 during a fibroblasts phase 216 of the proliferation stage 212(e.g., during a time when fibroblasts are present and active at thewound site in the proliferation stage 212) as also shown in FIG. 44.Each of the medicants A, B, B₁, C, C₁, D, D₁, E, F is discussed furtherbelow.

In one example, at least one medicant can be administered to tissueduring each of the hemostasis, inflammation, and proliferation stages208, 210, 212 of the wound healing to overall improve the wound healingprocess with all of the medicants shown in the second graph 202 beingadministered, e.g., the medicant A in the hemostasis stage 208, themedicants B, B₁, C, C₁, D, D₁ in the inflammation stage 210, and themedicants E, F in the proliferation stage 212. In another example, atleast one medicant can be administered to tissue during each of thehemostasis, inflammation, and proliferation stages 208, 210, 212 of thewound healing to overall improve the wound healing process without allof the medicants shown in the second graph 202 being administered, e.g.,the medicant A in the hemostasis stage 208, at least one of themedicants B, B₁, C, C₁, D, D₁ in the inflammation stage 210 (and in afurther example, at least two of the medicants B, B₁, C, C₁, D, D₁), andone or both of the medicants E, F in the proliferation stage 212. Thesubset of the medicants A, B, B₁, C, C₁, D, D₁, E, F administered can bedetermined on a case-by-case basis based on any one or more factors suchas wound type, wound size, surgeon preference, available medicants at atime of surgery, patient medical history, etc. In yet another example,at least one medicant can be administered to tissue during only one ortwo of the hemostasis, inflammation, and proliferation stages 208, 210,212 to improve select stages of the wound healing process (with animprovement in one stage being able to improve subsequent stage(s) ofthe wound healing process, as discussed above) without all of themedicants shown in the second graph 202 being administered. Further, themedicants can be administered in the selected one or two stages as shownin the second graph 202 (e.g., the medicant A in the hemostasis stage,the medicants B, B₁, C, C₁, D, D₁ in the inflammation stage 210, themedicants E, F in the proliferation stage 212) or can be selectivelyadministered in the selected one or two stages (e.g., the medicant A inthe hemostasis stage 208, at least one of the medicants B, B₁, C, C₁, D,D₁ in the inflammation stage 210 (and in a further example, at least twoof the medicants B, B₁, C, C₁, D, D₁), one or both of the medicants E, Fin the proliferation stage 212). The one or two of the stages 208, 210,212 in which medicant doses are administered can be determined on acase-by-case basis based on any one or more factors such as wound type,wound size, surgeon preference, available medicants at a time ofsurgery, patient medical history, etc.

As discussed herein, an adjunct material including one or more medicantsreleasable therefrom can be delivered to tissue, e.g., using a surgicalstapler. The adjunct material's one or more medicants can include eachof the medicants A, B, B₁, C, C₁, D, D₁, E, F being administered,whether it be all of the medicants A, B, B₁, C, C₁, D, D₁, E, F or asubset thereof. The administered ones of the medicants A, B, B₁, C, C₁,D, D₁, E, F can thus be delivered to the patient concurrent with a timeof the injury (t=0). As discussed herein, the adjunct material'smedicants can be releasable therefrom in a variety of ways. The timingof the release can allow the medicants to be administered to tissue atthe appropriate time in the wound healing process, as also discussedherein. The medicants A, B, B₁, C, C₁, D, D₁, E, F (or the selectedsubset thereof) can thus be simultaneously delivered to the patient butcan be released to the patient's tissue at different times and over timeto achieve the desired effects.

The medicant A configured to facilitate hemostasis can have a variety ofconfigurations. In general, the medicant A can include a hemostaticagent configured to promote hemostasis. The administration of themedicant A may thus help stop bleeding and help shorten a length of thehemostasis stage 208 and, accordingly, help the inflammation stage 210begin sooner than in typical wound healing. Examples of the medicant Ainclude fibrin and thrombin. Also, examples of hemostatic agentsconfigured to promote hemostasis and delivery thereof are described inU.S. Pat. Pub. No. 2013/0149343 entitled “Hemostatic BioabsorbableDevice with Polyethylene Glycol Binder” filed Dec. 13, 2011, U.S. Pat.No. 8,383,147 entitled “Reinforced Absorbable Synthetic Matrix ForHemostatic Applications” filed Aug. 22, 2012, and U.S. Pat. No.8,329,211 entitled “Reinforced Absorbable Multi-Layered Fabric ForHemostatic Applications” filed May 17, 2010, which are herebyincorporated by reference in their entireties.

The medicant A can be administered in a variety of ways. In one example,the medicant A can be administered from a vessel. The vessel can includea bioabsorbable or dissolvable coating, e.g., a saccharide coating,etc., surrounding the medicant A. The coating can be configured tobioabsorb/dissolve relatively quickly so as to be administered to thewounded tissue within minutes of the injury, e.g., within minutes oft=0. The medicant A's hemostatic effects can thus begin prior to thestart of the inflammation stage 210. As shown in FIG. 40 and FIG. 41,the dose of the medicant A can decrease over time as the agentdissipates in the tissue/the patient's body.

The medicants B, B₁, C, C₁ configured to facilitate inflammation caneach have a variety of configurations. In general, the medicants B, B₁,C, C₁ can each include an inflammatory agent configured to promoteinflammation. The medicants B, B₁, C, C₁ may thus help speed up theinflammatory process and, accordingly, help shorten the inflammationstage 210 as compared to typical wound healing, help the proliferationstage 212 begin sooner than in typical wound healing, help the tissuereach its minimum strength F3 sooner than when the minimum strength F4is reached in typical wound healing, and help shorten a period of timeat which the tissue is at its minimum strength F3 as compared to typicalwound healing. Examples of the medicants B, B₁, C, C₁ includepro-inflammatory medicants. In some aspects, the medicants B, B₁, C, C₁can each include the same agent. In other aspects, the medicants B, B₁can each include the same agent, and the medicants C, C₁ can eachinclude the same agent as each other that is a different agent than themedicants B, B₁. In still other aspects, the medicants B, B₁, C, C₁ caneach include a different agent from one another.

The medicants B, B₁, C, C₁ can each be administered in a variety ofways. In one example, the medicant B can be administered as a vesselwith the medicant B₁ being a coating of the medicant B vessel, and themedicant C can be administered as another vessel with the medicant C₁being a coating of the medicant C vessel. The dosages of the vesselmedicants B, C can be greater than the dosages of the coating medicantsB₁, C₁, as shown in FIG. 40 and FIG. 42, as vessel coatings typicallyinclude less substance than the vessel that they surround.

In one example, the medicant B₁ can be configured to begin release priorto the medicant B, which can be configured to begin release prior to themedicant C₁, which can be configured to begin release prior to themedicant C. The inflammatory medicants B, B₁, C, C₁ can thus beconfigured to be stagger-released with each medicants' dose peaking at adifferent time (e.g., at a different point along the time t axis of thesecond graph 202). The different peak dosages of the inflammatorymedicants B, B₁, C, C₁ can allow the medicants B, B₁, C, C₁ to have acumulative inflammatory dose, shown as “BC” in FIG. 40 and FIG. 42,greater than any of their individual doses. In other words, the peakdosages of the individual medicants B, B₁, C, C₁ can be timed tocontribute to an overall inflammatory dose “BC” greater than can beachieved individually with their doses. The inflammatory dose “BC” cangenerally have the shape of a square wave, as also shown in FIG. 40 andFIG. 42.

The inflammatory medicants B, B₁, C, C₁ can be configured to each beginrelease prior to the release of the other medicants effective in theinflammation stage 210, the medicants D, D₁ configured to inhibit MMPs.In this way, the tissue at the wound site can be allowed to be inflamedand approach its minimum tensile strength F3 a short time before daythree (t=3), at which time the macrophage phase 214 of the inflammationstage 210 generally begins and during which the medicants D, D₁ can beadministered.

The medicants D, D₁ configured to inhibit MMPs can each have a varietyof configurations. In general, the medicants D, D₁ can each include anagent configured to inhibit MMP, e.g., an MMP inhibitor. The medicantsD, D₁ can thus help less MMP be released in the inflammation stage 210,thereby allowing less of the ECM to be destroyed in the inflammationstage 210. The tissue at the wound site may thus be less torn down whilestill allowing the inflammatory process and, accordingly, allow thetissue to have more strength than in the typical wound healing process,e.g., F3>F4. Examples of the medicants D, D₁ include tissue matrixdegradation inhibitors that inhibit the action of MMPs and otherproteases. In one example, the medicants D, D₁ each include the sameagent, but the medicants D, D₁ can differ from one another in at leastsome examples.

The medicants D, D₁ can each be administered in a variety of ways. Inone example, each of the medicants D, D₁ can be administered via vessel.Each of the two vessels can include a coating configured to facilitaterelease of the medicants D, D₁ at the appropriate time in the woundhealing process, e.g., at a time after release of the inflammatorymedicants B, B₁, C, C₁, such as sometime 4 to 7 days after the injury(4<t<7). Examples of the coating include a copolymer having 90%polyglycolide (also referred to as polyglycolic acid (PGA)) and 10%polylactide (also referred to as polyactic acid (PCA)), such as Vicryl™Rapide.

In one example, the medicant D can be configured to begin release priorto the medicant D₁. The MMP-inhibiting medicants D, D₁ can thus beconfigured to be stagger-released with each medicants' dose peaking at adifferent time (e.g., at a different point along the time t axis of thesecond graph 202). The different peak dosages of the MMP-inhibitingmedicants D, D₁ can allow the medicants D, D₁ to have a cumulativeMMP-inhibiting dose, shown as “DD₁” in FIG. 40 and FIG. 43, greater thantheir individual doses. In other words, the peak dosages of theindividual medicants D, D₁ can be timed to contribute to an overallMMP-inhibiting dose “DD₁” greater than can be achieved individually withtheir doses.

The MMP-inhibiting medicants D, D₁ can be configured to each beginrelease prior to the release of the medicants E, F. In this way, thetissue at the wound site can be allowed to be inflamed and endure itsminimum tensile strength F3 before the proliferation stage 212 beginssometime during day four.

The medicant E configured to prevent inflammation can have a variety ofconfigurations. In general, the medicant E can include an agentconfigured to inhibit inflammation, e.g., an anti-inflammatory agent.The medicant E can thus be configured to help reduce inflammation at thewound site and, accordingly, help end the inflammation stage 210.Examples of the medicant E include diclofenac.

The medicant E can be administered in a variety of ways. In one example,the medicant E can be administered as a vessel. The vessel can include acoating configured to facilitate release of the medicant E at theappropriate time in the wound healing process, e.g., at a time afterrelease of the MMP-inhibiting medicants D, D₁, such as at least 4 daysafter the injury (4<t), e.g., sometime 7 to 10 days after the injury(7<t<10). Examples of the coating include a copolymer having 90% PGA and10% PCA and having a high molecular weight, e.g., a higher molecularweight than the coating used for the MMP-inhibiting medicants D, D₁ soas to be released thereafter.

The medicant F configured to facilitate tissue growth can have a varietyof configurations. In general, the medicant F can include an agentconfigured to promote tissue growth, e.g., a growth factor. The medicantF can thus be configured to help the tissue rebuild in the proliferationstage 212. Examples of the medicant F include TGF-β.

The medicant F can be administered in a variety of ways. In one example,the medicant F can be administered as a vessel. The vessel can include acoating configured to facilitate release of the medicant F at theappropriate time in the wound healing process, e.g., at a time afterrelease of the anti-inflammatory medicant E, such as at least 5 daysafter the injury (5<t), e.g., sometime 5 to 10 days after the injury(5<t<10). Examples of the coating include a copolymer having 65% PGA and35% PCA.

Implementations

In exemplary implementations described herein, a biocompatible adjunctcan be releasably retained on a surgical device and can be configured tobe delivered to tissue by deployment of staples in a cartridge body. Thebiocompatible adjunct can be releasably retained on one or both of atissue-facing surface of the cartridge body or a tissue-facing surfaceof the anvil. The adjunct can have a plurality of distinct regionshaving one or more medicants incorporated. Each of the regions can be ata different location on the adjunct and each region can have a differentadjunct construction. In this way, the medicants are configured torelease from the regions in various spatial and/or temporal manners.Such non-homogeneous release of the medicants with respect to at leastone of time of release and location of release can allow providing adesired therapeutic effect in a more controlled and targeted manner.

The adjunct and distinct regions thereof can be constructed in a varietyof different ways so as to deliver retained medicants into desiredlocations at a treatment site in manner that facilitate tissue in-growthor provide other effects to a wound. Different portions of the adjunctcan be configured to deliver different treatment effects to variouslocations in the wound. For example, the adjunct can be configured torelease medicant(s) near a tissue cut line or edge to promotehemostasis, portions of the adjunct disposed away from the cut line on atop side of the adjunct can deliver medicants to prevent adhesion, andportions of the adjunct disposed on a bottom side of the adjunct alsoaway from the cut line can deliver medicants to promote tissue growth.Any types of medicants can be delivered in this manner in a number ofdesired dosages. In this way, different portions of the same adjunct canprovide heterogeneous effects on wound healing.

In general, one or more medicants can be released in various spatial andtemporal patterns to promote one or more stages of wound healing, suchas hemostasis, inflammation, proliferation, and remodeling. FIG. 40above depicts wound healing over time. Various medicants can bereleasable from an adjunct to be administered to tissue at a treatmentsite to facilitate the wound healing stages. The timing of the releasecan allow the medicants to be administered to tissue at the appropriatetime in the wound healing process to achieve the desired effects, asdiscussed above in connection with FIG. 40.

At least one medicant can be released from an adjunct as a bolus dosesuch that the medicant is released substantially immediately upondelivery of the adjunct to tissue. Alternatively, the at least onemedicant can be released from the adjunct over a certain duration oftime, as a time release dosage. An adjunct in accordance with thedescribed techniques can release medicants as various combinations ofbolus doses and time release dosages, depending on a type of the wound,desired effects on the wound healing, patient's conditions, and otherfactors.

An adjunct in accordance with the described techniques can have avariety of different structures that form regions configured to elutemedicants therefrom in a heterogeneous manner. The regions can belayered, overlapped, intertwined, or otherwise structured. For example,the adjunct can be in the form of a fiber lattice and it can releasablyretain medicants in various ways—e.g., the medicants can be adhered tofibers in the fiber lattices, coated on the fibers, incorporated withinthe fibers, etc. Any other adjunct structures can be used additionallyor alternatively. A structure of an adjunct can be heterogeneous in anumber of different ways, including number, location, and position ofregions, manners in which medicants are releasable from the regions,types, number, dosages and effects provided by the medicants, and in anyother suitable ways.

FIG. 45 illustrates an example of an adjunct 600 that includes aplurality of layers or portions that can provide various medicantelution profiles. Similar to the adjunct 176 in FIG. 32, the adjunctincludes a top layer or portion 602 and a bottom layer or portion 604.In the example of FIG. 45, the top portion 602 has two regions 602 a,602 b and the bottom portion 604 has two regions 604 a, 604 b. The topportion's two regions 602 a, 602 b in this example can be similar to thetwo top portions 178 a, 178 b of the adjunct 176, and the bottomportion's two regions 604 a, 604 b can be similar to the two bottomportions of the adjunct 184 in FIG. 33. Furthermore, one or both regions604 a, 604 b of the bottom portion 604 can further include varioussub-regions, two of which are shown in FIG. 45 with reference numbers605, 607. Thus, the adjunct 600 can release medicants therefrom in anumber of different patterns.

Each of the regions 602 a, 602 b, 604 a, 604 b can have at least onemedicant releasably retained therein, which may or may not be in theform of a vessel. Each of the medicants of the regions 602 a, 602 b, 604a, 604 b can be the same as any one or more of the other medicants, oreach of the medicants can be different from any one or more of the othermedicants in any of one or more ways including type of medicant, dosageamount, and elution rate. Each of the regions 602 a, 602 b, 604 a, 604 bcan have degradation rates and/or other properties affecting medicantrelease that vary in a distinct or continuous manner. In this way, themedicants disposed within these regions can be releasable from one ormore of the regions in a non-homogeneous manner with respect to at leastone of time of release and location of release. The degradation ratesand distribution of the medicants within one or more of the regions 602a, 602 b, 604 a, 604 b can vary in a distinct or continuous manner suchthat the adjunct 600 can provide an elution profile shown in a graph 606in FIG. 46.

The graph 606 of FIG. 46 illustrates different rates or doses (“D”) ofmedicant release across the adjunct 600 from a left side 600L thereof toa right side 600R thereof. The spatial terms “left” and “right” are usedwith reference to the orientation of the adjunct 600 as shown in FIG. 46and are not intended to be limiting and absolute. The zero (“0”) alongthe x axis of the graph 606 represents a central area 608 of the adjunct600 centered around a mid-portion of the adjunct 600. The graph 606represents an exemplary elution profile that can represent release ofthe medicants, for example, after the adjunct 600 is delivered to tissueand the tissue to which the adjunct is delivered is cut (e.g., by acutting element of a surgical stapler).

As shown, the elution rate of the one or more medicants disposed in theadjunct 600 peaks at the right side 600R and curves downward toward theleft side 600L, where the elution rate is the lowest. Accordingly, ahigher dose of medicant(s) is delivered the closer the medicant(s) areto the right side 600R of the adjunct 600. In this way, when the rightside 600R is positioned along the cut line or cut edge of the tissue,more medicant can be delivered along the cut tissue edge. In anexemplary implementation, the one or more medicants disposed in thefirst portion 602 a of the top portion 602 of the adjunct 600 caninclude a hemostatic agent, which may allow a relatively high dose ofthe hemostatic agent to be delivered to tissue to facilitate bloodclotting therealong in accordance with the elution profile shown in thegraph 606.

FIG. 47 illustrates another graph 610 showing another elution profile (adose D versus a location within the adjunct 600) that various regions ofthe adjunct 600 can provide together, in accordance with degradationrates of polymers and distribution of the one or more medicants withinthe regions 602 a, 602 b, 604 a, 604 b. The graph 610 is similar to thegraph 606 of FIG. 46 in that the elution rate of the one or moremedicants disposed in the adjunct 600 peaks at the right side 600R andslopes downward toward the left side 600L, where the elution rate is thelowest. The slope in the graph 610 represents a linear function, unlikethe curve in the graph 606.

FIG. 48 illustrates another graph 612 showing another elution profilethat the adjunct 600 can provide according to degradation rates andother properties of the regions 602 a, 602 b, 604 a, 604 b. As shown inthe graph 612, the central area 608 of the adjunct 600 can have thehighest elution rate. This area configured to release the highest dosageof one or more medicants can be disposed, for example, along a plannedcut line of tissue such that the highest dosage of the one or moremedicants is delivered to the cut line created by a cutting element of asurgical stapler. For example, a relatively high dose of a hemostaticagent, an antimicrobial agent, an antifungal agent, and/or an antiviralagent can be delivered from the central area 308 of the adjunct 600.Examples of applications where it can be advantageous to deliver thehighest dosage of one or more medicants along the cut line are furtherdescribed in U.S. patent application No. [ ] entitled “Adjunct MaterialTo Promote Tissue Growth” filed on even date herewith Attorney DocketNo. 47364-162F01US (END7625USNP), which is hereby incorporated byreference in its entirety. As shown in FIG. 48, the elution ratedecreases from the central area 608 towards both the left and rightsides 600L, 600R of the adjunct 600.

Multiple doses of a medicant can be released from one or more regions ofan adjunct at different times and over different periods of time toachieve a cumulative dose of the medicant. Examples of graph ofcumulative doses of various medicants are described in above-mentionedU.S. patent application No. [ ] entitled “Adjunct Material To PromoteTissue Growth” filed on even date herewith Attorney Docket No.47364-162F01US (END7625USNP).

In some exemplary implementations, adjuncts configured to release atleast one medicant therefrom in a variety of temporal and spatialpatterns can be in the form of matrix metalloproteinase (MMP) inhibitingadjuncts for surgical devices. As discussed above, in the inflammationstage of the four wound healing stages (hemostasis, inflammation,proliferation, and remodeling), MMPs can be released to facilitatedestruction of the ECM in the proliferation stage. As also discussedabove, during the proliferation stage, an epithelialization processoccurs in which parts of the ECM are destroyed to facilitate themigration of epithelial cells over the wound, and fibroblastsdifferentiate into myofibroblasts to form a protective outer layer overthe wound. In the case of a patient's tissue being wounded by havingstaples applied thereto, the epithelialization process generally occursat the tissue along the one or more lines of staples applied to thetissue. The more of the ECM that is destroyed and the longer theepithelialization process lasts, the more likely the patient willexperience one or adverse effects of wound healing, e.g., infection,scarring, pain, etc. It may therefore be advantageous to reduce anamount of the ECM that is destroyed and/or to a length of theepithelialization process. In other words, it may be advantageous toaccelerate the start of the proliferation stage and to reduce itsduration and, consequently, reduce an amount of time before theremodeling stage begins. The patient can thus be less likely toexperience complications resulting from the wound.

Thus, an implantable adjunct can be configured to releasably retain atleast one medicant, such as a tissue matrix degradation inhibitor, thatcan accelerate the inflammation stage and/or the proliferation stageand, accordingly, reduce an amount of time before the remodeling stagebegins. The at least one medicant can be configured to be released alonga staple line defined by staples, which may help target the at least onemedicant's desired functionality to where MMPs are released and wherethe epithelialization process generally occurs at the wounded tissue.The adjunct and the at least one medicant releasable therefrom may thushelp prevent the tissue along the staple line from becoming too weakduring the wound healing process.

The tissue matrix degradation inhibitor can be configured to inhibit MMPand, hence, be configured to allow less of the ECM to be destroyed. TheMMP inhibitor can be introduced to the tissue via the adjunct andthereby limit the enzymatic destruction of the underlying collagenmatrix, which as discussed above can be overly accelerated by anoveractive inflammation response and by macrophages. The MMP inhibitorcan thus delay the destruction and therefore delay strength loss at thewound along the staple line long enough for the new collagen being laiddown to reinforce the staple line and thereby help prevent staplefailure.

Examples of adjuncts that can release at least one medicant in variousspatial and temporal patterns include adjunct 108 in FIG. 9. As shown inFIG. 9, the adjunct 108 has multiple reservoirs or regions formed indifferent location within the adjunct 108, five of which are shown asregions 109 a, 111 a, 113 a, 109 b, 111 b that carry respective vessels110, 112, 114, 110, 112. The vessels 110, 112, 114 can releasably retaintherein first, second, and third medicants, respectively. Thus, theregions 109 a, 109 b can be configured to release the first medicant,the regions 111 a, 111 b can be configured to release the secondmedicant, and the region 113 a can be configured to release the thirdmedicant. Each of the regions 109 a, 109 b can be configured to commencerelease of the first medicant substantially immediately upon delivery ofthe adjunct 108 to tissue, each of the regions 111 a, 111 b can beconfigured to commence release of the second medicant after release ofthe first medicant, and the region 113 a can be configured to commencerelease of the third medicant after release of the second medicant. Inthis way, different medicants can be delivered at appropriate times todesired locations in tissue being treated.

In some implementations, the 109 a, 109 b regions can be configured tocomplete delivery of the first medicant within about one day afterdelivery of the adjunct 108 to tissue, the regions 111 a, 111 b can beconfigured to deliver of the second medicant within a period of aboutone day after delivery of the adjunct 108 to tissue to about three daysafter delivery of the adjunct material to tissue, and the region 113 acan be configured to initiate delivery of the third medicant withinabout three days after delivery of the adjunct 108 to tissue. In suchimplementations, for example, the first medicant configured to commenceits release substantially immediately upon delivery of the adjunct 108to tissue can be a hemostatic agent or other agent that is released atan acute dose (bolus release). The second medicant can be ananti-inflammatory agent. Also, at least one of the second and thirdmedicants can be at least one medicant such as, for example, MMPinhibiting agent configured to reduce a length of the epithelializationprocess, with the coating associated therewith being on the side 108 a,108 b of the adjunct 108 facing a staple line.

Other examples of adjuncts that can spatially and temporary release atleast one medicant to provide a desired therapeutic effect includeadjunct 100 of FIG. 40, adjunct 122 of FIG. 15, adjunct 116 of FIG. 12,adjunct 162 of FIG. 26, and adjunct 176 of FIG. 32. Examples of MMPinhibiting adjuncts are described in U.S. patent application No. [ ]entitled “Matrix Metalloproteinase Inhibiting Adjuncts For SurgicalDevices” filed on even date herewith Attorney Docket No. 47364-167F01US(END7630USNP), which is hereby incorporated by reference in itsentirety.

In some implementations, an adjunct can be configured to releasablyretain at least one medicant as described, for example, in U.S. Pat.Appl. Pub. No. 2013/0149343 entitled “Hemostatic Bioabsorbable DeviceWith Polyethylene Glycol Binder” filed Nov. 13, 2011, U.S. Pat. No.8,383,147 entitled “Reinforced Absorbable Synthetic Matrix ForHemostatic Applications” filed Aug. 22, 2012, U.S. Pat. No. 8,319,211entitled “Reinforced absorbable multi-layered fabric for hemostaticapplications” filed May 17, 2010, U.S. Pat. No. 8,273,369 entitled“Reinforced Absorbable Synthetic Matrix For Hemostatic Applications”filed May 17, 2010, which are hereby incorporated by reference in theirentireties. The entire adjunct or a portion thereof can be in a form ofEVARREST™ Fibrin Sealant Patch manufactured by Ethicon Biosurgery,Division of Ethicon, Inc. In at least some of such implementations, theadjunct can include at least one medicant, such as a hemostatic or otheragent, in a form of powder that is coupled to an absorbable filmconfigured to elude an MMP inhibitor which starts on day one after theadjunct is delivered to tissue and can end until the end of day three.In some implementations, an adjunct can include multiple layersreleasably retaining at least one medicant Each of the layers can beformed from respective one or more bioabsorbable polymer and can retaina medicant that is different from medicants retained by other layers.Depending on degradation rates of the bioabsorbable polymer and otherfactors, the adjunct can release the medicants in various patterns. Forexample, adjunct release pattern can include multiple mini-boli ofdifferent medicants released at different times. As another example,medicants can be released at different times over longer time periodssuch that release of two or more medicants can overlap in time.Furthermore, the medicants can be disposed at different locations withinan adjunct and two or more medicants can release at different locationsof the adjunct as bolus doses or time release dosages. Examples ofadjuncts that include multiple layers retaining at least one medicantinclude adjunct 108 in FIGS. 9-11 and adjunct 116 in FIGS. 12-14.

In some exemplary implementations, an adjunct can be in the form of afiber lattice including multiple fibers formed from a biodegradablepolymer. The fiber lattice can retain one or more medicants therein suchthat the medicants are releasably coupled to fibers of the fiber latticeby being “trapped” within the fibers. For example, the adjunct canretain the medicant due to a conformation of the fibers (e.g., thefibers can be wound together or woven into a sheet mesh or otherstructures). The medicant can be located within pores or otherreservoirs formed in the adjunct. Also, the fibers can be tightly wound,woven, knitted, or otherwise interconnected such that medicant(s) can beretained in the adjunct by being held within the tightly interconnectedfibers.

Degradation of the fiber lattice causes the adjunct to change itsconformation, such as by the action of water and/or other agents thatthe adjunct is subjected to at a treatment site. The change of theconformation can involve, for example, one or more of degradation of oneor more layers of the adjunct, opening of pores, loosening of thefibers' interconnection, unwinding of the fibers, or other changes inthe adjunct relative to its original conformation. As the adjunctchanges its conformation, release of one or more medicants can bereleased from one or more locations within the adjunct that becomeexposed to water and/or other agents present at an environment aroundthe adjunct in the treatment site. Examples of adjuncts that canreleasably retain one or more medicants in the above-described mannerinclude adjunct 162 in FIGS. 26 and 27 and adjunct 166 in FIGS. 28 and29. An adjunct such as the adjunct 162 or adjunct 166 can include aplurality of regions includes a fiber lattice region that is watersoluble and degrades more quickly than a second one of the regions.

In some exemplary implementations, an adjunct can include a copolymer ormultiple bioabsorbable copolymers that can carry an effective dose of atleast one medicant. The polymers can be different polymers or differentversions of the same bioabsorbable polymer. For example, an adjunct caninclude both lower and higher molecular weight versions of the samebioabsorbable polymer. The at least one medicant can be incorporatedinto the one or more copolymers such that, when the copolymer(s)degrade, the at least one medicant is being released under control ofthe copolymers' degradation rate and other factors. The copolymer(s) canbe in the form of two or more layers formed such that the layers havedifferent degradation rates and retain different concentrations of thesame or different medicant(s). The layers of an adjunct can be formedfrom the same type of a bioabsorbable polymer that is treated such thateach of the layers has degradation rate different from that of one ormore of other layers. In general, the at least one medicant can bedispersed within one or more copolymers in a number of different ways.For example, the at least one medicant can be dispersed within one ormore copolymers in a substantially homogeneous manner across theadjunct. Alternatively, the at least one medicant can form one or morehigher-concentration areas within the adjunct—e.g., some of thelocations of the adjunct can release more medicants than other areas.

Examples of adjuncts that can releasably retain at least one medicantwithin layers of one or more copolymers include adjunct 116 in FIGS.12-14. As described above, the adjunct 116 has first (top) and second(bottom) layers 118, 120 formed from absorbable polymers havingdifferent degradation rates. The first layer 118 can be a low molecularweight absorbable polymer that absorbs during a first time period afterthe adjunct 116 is delivered to tissue and the second layer 120 can be ahigh molecular weight absorbable polymer that absorbs during a secondtime period after the first time period is completed. As the first andsecond layers 118, 120 absorb in accordance with their degradationrates, they release respective medicant(s) incorporated therein.Examples of implantable medical devices formed of block co-polymers aredescribed in U.S. Pat. No. 8,652,506 entitled “Bio-degradable BlockCo-polymers For Controlled Release” filed on Jun. 5, 2008, which ishereby incorporated by reference in its entirety.

As mentioned above, an adjunct in accordance with the describedtechniques can retain medicants at different locations throughout theadjunct. The spatial distribution of the medicants can vary in differentways to provide different patterns of medicant release to achievedesired effect. Various medicants can be disposed at different locationswithin the adjunct and targeted delivery of the medicants can beaccomplished in a number of different ways. For example, FIGS. 9-11illustrate adjunct 108 having multiple reservoirs or regions 109 a, 111a, 113 a, 109 b, 111 b disposed at different locations and releasablyretaining therein different medicants. The regions are covered bycoatings A1, B1, C1 have different degradation or absorption rates thatcontrol release of the medicants from different locations of the adjunct108 at different times. Opposite sides 108 a, 108 b of the adjunct 108are configured to release one or more medicants in different patternssuch that the medicants can be delivered at appropriate times to desiredlocations in tissue being treated. For example, in some implementations,at least one first medicant released from regions 109 a. 109 b on thefirst side 108 a of the adjunct 108 can be at least one agent thatpromotes healing, whereas at least one second medicant released fromregions 111 a, 111 b on the second side 108 b of the medicant can be atleast one medicant that prevents adhesion of tissue to the adjunct 108.In such implementations, the first side 108 a can be a tissue contactingsurface.

An adjunct can be configured such that at least one medicant is releasedtherefrom at a cut line formed. e.g., by a stapler's cutting element,and different medicants are released at locations in the adjunct awayfrom the cut line. Also, similar to the adjunct 108 of FIGS. 9-11,different sides of an adjunct can be configured to deliver differentmedicants therefrom, to provide a desired location-specific effect ontissue.

In some implementations, a tissue cutting element of a surgical staplingdevice can be configured to pass through a slot formed along alongitudinal axis thereof of a cartridge body. An adjunct can includefirst, second, and third portions releasably retaining first, second,and third medicants, respectively. The first region can be positionedwithin a central portion of the adjunct on either side of the slot andit can be configured to be separated by passage of the tissue cuttingelement through the slot such that release of the first medicantcommences substantially simultaneously upon passage of the cuttingelement through the first region. The second region can be in contactwith a surface of the cartridge body, and the second medicant can beeffective to inhibit tissue growth adjacent the second region. The thirdregion can be opposite the second region and it can be effective topromote tissue growth.

FIG. 49 illustrates an implementation of an adjunct 620 formed from aplurality of fibers and including a plurality of heterogeneous sectionsor regions 624 a, 624 b, 624 c, 624 d, 624 e. It should be appreciated,however, that adjuncts can have another number of heterogeneous regions.In the example illustrated, the first region 624 a is located on a topside 622 a and on opposed lengthwise sides of the adjunct 620 and isconfigured to discourage tissue growth. e.g., to prevent adhesion. Thefirst region 624 a can be configured to discourage tissue growth in avariety of ways. Examples of ways in which tissue growth can bediscouraged are discussed in mentioned-above U.S. patent application No.[ ] entitled “Adjunct Material To Promote Tissue Growth,” filed on evendate herewith, Attorney Docket No. 47364-162F01US (END7625USNP). Thefirst region 624 a can have at least one first medicant (not shown)releasably retained therein that is configured to discourage tissuegrowth, such as an anti-adhesion agent.

The second and third regions 624 b, 624 c are each located on a bottomside 622 b of the adjunct 620 and are each configured to encouragetissue growth. The second and third regions 624 b, 624 c can beconfigured to encourage tissue growth in a variety of ways, asdiscussed, for example, in U.S. patent application No. [ ] entitled“Adjunct Material To Promote Tissue Growth,” filed on even dateherewith, Attorney Docket No. 47364-162F01US (END7625USNP). The secondand third regions 624 b, 624 c can have at least one second medicant(not shown) releasably retained therein that is configured to encouragetissue growth, such as a growth factor. Further, the second and thirdregions 624 b. 624 c can have the same structure as one another and canhave the same medicant releasably retained therein, but, in otherimplementations, the second and third regions 624 b, 624 c can each beconfigured to encourage tissue growth but differ from one another instructure and/or in retained medicant(s).

As illustrated, a fourth region 624 d is disposed between the second andthird regions 624 b, 624 c on the bottom side 622 b. In this illustratedimplementation, the fourth region 624 d is configured to facilitatehemostasis. FIG. 49 also shows the fourth region 624 d underlying thefirst and fifth regions 624 a, 624 e by a dotted line on the top side622 a of the adjunct 620. As illustrated, the fourth region 624 dextends along a central longitudinal portion of the adjunct 620, whichfacilitates delivery of its hemostatic properties to tissue. The fourthregion 624 d can be configured to facilitate hemostasis growth in avariety of ways, as discussed, for example, in U.S. patent application [] entitled “Adjunct Material To Promote Tissue Growth,” filed on evendate herewith, Attorney Docket No. 47364-162F01US (END7625USNP). Thefourth region 624 d has a third medicant 626 (shown in FIG. 50 and FIG.51) releasably retained therein that is configured to facilitatehemostasis, such as a hemostatic agent.

As shown in FIG. 49, the fifth region 624 e is located in an interiorarea of the adjunct 620 in a cavity defined by the top side 622 a,opposed lengthwise sides, and bottom side 622 b of the adjunct 620, andis configured to space apart the top and bottom sides of the adjunct 620to thereby space apart the tissue growth-encouraging and tissuegrowth-discouraging portions of the adjunct 620. In other words, thefifth region 624 e is configured to space the second and third regions624 b. 624 c apart from the first region 624 a. The fifth region 624 ecan have a fourth medicant (not shown) releasably retained therein. Thefourth medicant can include, for example, an anti-adhesion agent suchas, for example, oxidized regenerated cellulose (ORC), and/or anotherhemostatic agent.

The adjunct 620 can be releasably coupled to a stapler (e.g., to an endeffector of a stapler and/or to a cartridge retainable in a stapler) sothat the adjunct 620 can be positioned relative to tissue to which thestapler applies staples and the adjunct 620. In general, the position ofthe adjunct 620 relative to tissue can include the bottom side 622 bthereof facing the tissue and the top side 622 a thereof facing awayfrom the tissue. The hemostasis-encouraging region 624 d and the tissuegrowth-encouraging regions 624 b, 624 c can thus be facing the tissue soas to facilitate delivery of their respective medicants to the tissue,and the tissue growth-discouraging section 318 a can thus be facing awayfrom the tissue to this deliver its medicant thereto.

In some implementations, the second and third tissue growth-encouragingregions 624 b, 624 c can include a plurality of medicants configured toevoke healing processes at portions of the regions 624 b. 624 c disposedat both sides of and away from the fourth region 624 d. Thus, while thethird medicant 626 released from the fourth region 624 d is configuredto facilitate hemostasis, the plurality of medicants can be releasedfrom different locations of the second and third regions 624 b, 624 c atdifferent times. The medicants can be retained within the second andthird regions 624 b, 624 c in a number of different ways as describedherein, and one or more of the medicants can be carried within vessels.For example, the medicants can be located in pores or reservoirsdistributed throughout the second and third regions 624 b, 624 c in adesired pattern. In some aspects, the reservoirs can be formed in asimilar manner as in the adjunct 108 of FIGS. 9-11. The pattern of thereservoirs and the way in which the medicants are configured to bereleased from the reservoirs can be such that, for example, medicantsfacilitating subsequent wound healing stages are released at times andfor time periods that facilitate progression of the wound healingstages. The reservoirs can be located within the adjunct to as to allowrelease of appropriate medicants at locations of the wound where thosemedicants are beneficial. The medicants can be released from thereservoirs in a variety of ways. e.g., as one or more coatings of thereservoirs rupture, as adjunct's portions (e.g., fibers, fiber lattices,fiber meshes, etc.) retaining the medicant(s) disintegrate and/or changetheir conformation, and in other manners as described herein.

FIG. 50 and FIG. 51 illustrate an example of the adjunct 620 stapled toa tissue 628 with a plurality of staples 630. FIG. 50 and FIG. 51 showthe third medicant 626 being released from the fourth region 624 d alonga cut edge 620 c of the adjunct 620 and a cut edge 628 c of the tissue628, the cut edges 320 c, 628 c having been formed by a stapler'scutting element during the stapling process. In the illustratedimplementation, a stapler's cutting element can translate longitudinallyalong a center of a staple cartridge. The adjunct 620 can be releasablyretained on the cartridge and/or on an end effector having the cartridgeseated therein with the fourth region 624 d aligned with thelongitudinal path of the cutting element. The fourth region 624 dextending along the central longitudinal portion of the adjunct 620 mayfacilitate such placement. Thus, when the cutting element translatesalong the cartridge to cut the tissue 628, the cutting element also cutsthrough the fourth region 624 d, which may facilitate leakage, dripping,and/or other release of the third medicant 626 from the fourth region624 d. In other words, the cutting of the fourth the fourth region 624 dcan help the third medicant 626 exit the adjunct 620. Further, thelocation of the fourth region 624 d above the tissue 628, as shown inFIG. 50 and FIG. 51, can help the third medicant 626 to drip orotherwise flow down onto the tissue 628. In particular, the thirdmedicant 626 can be advantageously delivered to the cut edge 628 c ofthe tissue 628 which is an area that is most susceptible to bleeding andhence is most in need of the hemostatic properties provided by the thirdmedicant.

As illustrated in FIG. 51, the second region 624 b can be configured tounwind or fray along a side 636 thereof facing the tissue 628, e.g., theside defining part of the bottom side 622 b of the adjunct 620. In otherwords, fibers of the second region 624 b can be configured to “unwind.”The unwinding or fraying can facilitate release of the second medicantfrom the second region 624 b. The unwinding or fraying can be triggeredby contact of the fibers with fluid, e.g., with moisture of the tissue628. The third region 624 c can be similarly configured to unwind orfray, whereas the first region 624 a can be configured to not unwind orfray, thereby facilitating anti-adhesion.

In the examples of FIG. 49, FIG. 50, and FIG. 51, the adjunct 620 has agenerally rectangular shape to facilitate its use with a linear stapler.However, an adjunct that can facilitate anti-adhesion and encouragetissue in-growth and hemostasis can have other different shapes, forexample, shapes that allow use of the adjunct with a circular stapler.

In some implementations, an adjunct configured to release at least onemedicant therefrom in a heterogeneous manner can be structured suchthat, when a cutting element (e.g., knife) translates along a cartridgeand cuts tissue and a portion of an adjunct (e.g., its central portion),the cutting activates release of multiple medicants from the adjunct.The medicants can be released such that two or more of the medicants areblended together. In the blend, the medicants (e.g., fibrin andthrombin, etc.) can enhance one another's activation raters. The cuttingelement (e.g., knife and/or staples) can have features that enhance thedistribution and/or mixing of the medicants.

Examples of adjunct materials that can release a plurality of medicantsare described in U.S. Pat. Appl. Pub. No. 2013/0256367 entitled “TissueThickness Compensator Comprising A Plurality of Medicaments” filed onMar. 28, 2012, which is hereby incorporated by reference in itsentirety. As described in U.S. Pat. Appl. Pub. No. 2013/0256367, amaterial can be provided that is configured to be disposed on acartridge and that can include an outer layer encompassing an innerlayer that includes medicants, such as freeze-dried thrombin and/orfibrin. When the outer layer, which can be water impermeable, ispunctured by staples, water and/or other agents in the externalenvironment at a treatment site can infiltrate the inner layers andcause the medicant to release from the adjunct. Furthermore, in someimplementations, the staples inserted into the inner and outer layerscan be disposed around the inner layer and the staples and can besealed. Another example of an adjunct that can release a plurality ofmedicants is described in U.S. Pat. No. 7,708,180 entitled “SurgicalFastening Device With Initiator Impregnation Of A Matrix Or Buttress ToImprove Adhesive Application” filed on Nov. 9, 2006, which is alsohereby incorporated by reference in its entirety.

In some implementations, at least one medicant can be releasablydisposed in a dispenser in an elongate shaft of a surgical instrument.Examples of such surgical instruments are described in U.S. Pat. No.8,905,977 entitled “Surgical Stapling Instrument Having An ElectroactivePolymer Actuated Medical Substance Dispenser” filed on Jun. 1, 2005, andU.S. Pat. No. 8,215,531 entitled “Surgical Stapling Instrument Having AMedical Substance Dispenser” filed on Jan. 29, 2010, which are herebyincorporated by reference in their entireties. Movement of a cuttingelement, such as knife, can release the at least one medicant containedin the shaft of the surgical instrument. If the surgical instrument is amulti-fire device, the at least one medicant can be reloaded into theinstrument after each application to tissue. Alternatively, a dispenser(e.g., syringe or other device) releasably carrying the medicant anddisposed within a shaft of a surgical instrument can be replaced aftereach use.

The techniques described in the above-mentioned references can be usedin conjunction with the adjunct 620 shown in FIG. 49, FIG. 50, and FIG.51. In this way, a surgical instrument can include a biocompatibleadjunct releasably retained on a cartridge body retaining at least onefirst medicant, and the surgical instrument can further include at leastone second medicant disposed within an elongate shaft. Actuation of atissue cutting element of the surgical instrument can cause both thefirst and second medicants to be delivered to tissue. In someimplementations, one of the first and second medicants can affectactivity of another of the first and second medicants.

In some implementations, as mentioned above, an adjunct can retaintherein a plurality of medicants at different locations thereof, suchthat the medicants are configured to release from the adjunct inspatially heterogeneous patterns. For example, the adjunct can include aplurality of layers (e.g., concentric and/or stacked layers, orotherwise structured layers) that can each releasably retain at leastone medicant therein. In some aspects, each of the layers can retain adifferent medicant. Regardless of the specific configuration of theadjunct, different medicants retained therein can be delivered todesired locations in tissue being treated. Examples of such adjunctsinclude adjunct 176 in FIG. 32, adjunct 190 in FIG. 37, adjunct 194 inFIG. 38, and adjunct 197 in FIG. 39. In these adjuncts, and any otheradjuncts in accordance with the techniques described herein, theplurality of medicants being released from one or more portions of theadjuncts in a non-homogeneous manner with respect to at least one oftime of release and location of release can deliver various effects totissue. For example, the medicants can upregulate anti inflammation orpro-healing agents. As another variation, one medicant can upregulatepro-healing response such as VEGF, FGF, or TGF, and another medicant candown regulate anti-healing response such as specific MMPs, IL, or TNFa.Any other desired effects can be provided to tissue being treated.

At least one medicant can be incorporated into an adjunct at locationswithin the adjunct that facilitate delivery of the at least one medicantto a desired tissue location. As mentioned above, a medicant releasablyretained by an adjunct can elute from the adjunct when a tissue cuttingelement passes through a slot in a cartridge body of a surgicalinstrument and thereby cuts tissue and a region of the adjunctpositioned within a central portion of the adjunct on either side of theslot. Additionally or alternatively, staples configured to deliver anadjunct to tissue can be configured to thereby cause at least onemedicant retained by the adjunct to be released from one or moreportions of the adjunct. Furthermore, the at least one medicant can beassociated with the staples. Examples of surgical staples associatedwith at least one medicant are described, for example, in U.S. patentapplication Ser. No. [ ] entitled “[_],” filed on even date herewith,Attorney Docket No. 47364-166F01US (END7629USNP), which is herebyincorporated by reference in its entirety.

FIG. 52 and FIG. 53 illustrate an exemplary adjunct 650 that can beconfigured to be disposed over an anvil 652 of a surgical instrument.The adjunct 650 can be retained on the anvil 652 using a retainercomponent 654 which can have a variety of different configurations.However, in some implementations, the retainer component 654 may not beused. As shown, the adjunct 650 can include different doses of first andsecond medicants 656, 658 that can be released therefrom when theadjunct 650 is delivered to tissue. As also shown, the adjunct 650 canbe configured such that regions with the first medicant 656 are disposedin staple forming pockets 652 a formed on the surface of the anvil 652and regions with the second medicant 658 are disposed in areas of theanvil 652 between the staple forming pockets 652 a. Thus, the firstmedicant 656 is disposed a larger amount than the second medicant 658.When staples (not shown) are fired from a staple cartridge of thesurgical instrument and are formed in the staple forming pockets 652 a,the staples can puncture the adjunct 650 at its areas disposed over thestaple forming pockets 652 a and thereby release the first medicant 656disposed at those areas. The second medicant 658 can be configured to bereleased in a variety of other manner as described herein. Furthermore,in some cases, release of the first medicant 658 from the adjunct 650can affect release of the second medicant 658 therefrom.

It should be appreciated that the first and second medicants 656, 658can be releasably disposed directly on the anvil 652 such that they arenot retained by any adjunct. In such implementations, the retainercomponent 654 as shown in FIG. 52 and FIG. 53, or any other type of aretainer, can releasably retain the first and second medicants 656, 658on the surface of the anvil 650.

At least one medicant can be disposed within an adjunct at locationsthereof corresponding to various locations on a surface of an anvil or acartridge. For example, patterns in which the at least one medicant isreleasably retained in the adjunct can correspond to a pattern ofstaples to be delivered from the cartridge. At least one medicant can bedisposed in areas of the adjunct to be punctured by staples and at leastone other medicant can be disposed in areas of the adjunct disposedbetween the areas to be punctured by staples. Also, the at least onemedicant to be delivered to tissue by deployment of staples can bedisposed within the adjunct in patterns corresponding to a shape ofstaple forming pockets. Examples of such adjuncts are described in U.S.patent application Ser. No. 14/498,145 entitled “Method For Creating AStaple Line” filed on Sep. 26, 2014, which is hereby incorporated byreference in its entirety.

A person skilled in the art will appreciate that the present inventionhas application in conventional minimally-invasive and open surgicalinstrumentation as well application in robotic-assisted surgery.

The devices disclosed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Thoseskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed is:
 1. A staple cartridge assembly for use with asurgical stapler, comprising: a cartridge body having a plurality ofstaple cavities, each staple cavity having a surgical staple disposedtherein; a biocompatible adjunct material releasably retained on thecartridge body and configured to be delivered to tissue by deployment ofthe staples in the cartridge body, the adjunct material having aplurality of distinct regions, wherein each region is at a differentlocation on the adjunct material and each region has a different adjunctconstruction; and an effective amount of at least one medicant disposedwithin and releasable from at least two of the regions, each of the atleast one medicants being effective to provide a desired effect, andeach of the at least one medicants being releasable from one of theregions in a non-homogeneous manner with respect to at least one of timeof release and location of release.
 2. The cartridge assembly of claim1, wherein a first one of the regions contains a first medicant, asecond one of the regions contains a second medicant, and a third one ofthe regions containing a third medicant, each region being at adifferent location within the adjunct material.
 3. The cartridgeassembly of claim 2, wherein the first region is configured to commencerelease of the first medicant substantially immediately upon delivery ofthe adjunct material to tissue, the second region is configured tocommence release of the second medicant after release of the firstmedicant, and the third region is configured to commence release of thethird medicant after release of the second medicant.
 4. The cartridgeassembly of claim 3, wherein the first region is configured to completedelivery of the first medicant within about one day after delivery ofthe adjunct material to tissue, the second region is configured todeliver of the second medicant within a period of about one day afterdelivery of the adjunct material to tissue to about three days afterdelivery of the adjunct material to tissue, and the third region isconfigured to initiate delivery of the third medicant within about threedays after delivery of the adjunct material to tissue.
 5. The cartridgeassembly of claim 3, wherein the first medicant is a hemostatic agent.6. The cartridge assembly of claim 3, wherein the second medicant is ananti-inflammatory agent.
 7. The cartridge assembly of claim 2, whereinthe cartridge body has a slot formed along a longitudinal axis thereofthat is configured to allow passage of a tissue cutting elementtherethrough, and wherein: the first region is positioned within acentral portion of the adjunct material on either side of the slot andis configured to be separated by passage of the cutting element throughthe slot such that release of the first medicant commences substantiallysimultaneously upon passage of the cutting element through the firstregion; the second region is in contact with a surface of the cartridgebody, and the second medicant is effective to inhibit tissue growthadjacent the second region; and the third region is opposite the secondregion, and the third medicant is effective to promote tissue growth. 8.The cartridge assembly of claim 7, wherein the third medicant isreleased after the first medicant.
 9. The cartridge assembly of claim 1,wherein the adjunct material is formed of a fiber lattice, and each ofthe plurality of regions is formed of a different fiber lattice.
 10. Thecartridge assembly of claim 9, wherein the at least one medicant isadhered to fibers in the fiber lattices, and each of the plurality ofregions contains a different medicant.
 11. The cartridge assembly ofclaim 10, wherein the medicant is coated on the fibers.
 12. Thecartridge assembly of claim 9, wherein at least one fiber lattice hasmultiple drugs present in multiple degradable layers fibers within theat least one fiber lattice.
 13. An end effector for a surgicalinstrument, comprising: a first jaw having a cartridge body removablyattached thereto, the cartridge body having on a tissue-facing surfacethereof a plurality of staple cavities configured to seat staplestherein; a second jaw having an anvil with a plurality of staple formingcavities formed on a tissue-facing surface thereof, wherein at least oneof the first and second jaws is movable relative to the other; abiocompatible adjunct material releasably retained on at least one ofthe tissue-facing surfaces of the cartridge body and the anvil, andconfigured to be delivered to tissue by deployment of the staples in thecartridge body, the adjunct material having a plurality of distinctregions, wherein each region is at a different location on the adjunctmaterial and each region has a different adjunct construction; and aneffective amount of at least one medicant disposed within and releasablefrom at least two of the regions, each of the at least one medicantsbeing effective to provide a desired effect, and each of the at leastone medicants being releasable from one of the regions in anon-homogeneous manner with respect to at least one of time of releaseand location of release.
 14. The end effector of claim 13, wherein afirst one of the regions contains a first medicant, a second one of theregions contains a second medicant, and a third one of the regionscontaining a third medicant, each region being at a different locationwithin the adjunct material.
 15. The end effector of claim 14, whereinthe first region is configured to commence release of the first medicantsubstantially immediately upon delivery of the adjunct material totissue, the second region is configured to commence release of thesecond medicant after release of the first medicant, and the thirdregion is configured to commence release of the third medicant afterrelease of the second medicant.
 16. The end effector of claim 15,wherein the first region is configured to complete delivery of the firstmedicant within about one day after delivery of the adjunct material totissue, the second region is configured to deliver of the secondmedicant within a period of about one day after delivery of the adjunctmaterial to tissue to about three days after delivery of the adjunctmaterial to tissue, and the third region is configured to initiatedelivery of the third medicant within about three days after delivery ofthe adjunct material to tissue.
 17. The end effector of claim 15,wherein the first medicant is a hemostatic agent.
 18. The end effectorof claim 15, wherein the second medicant is an anti-inflammatory agent.